clinical presentation of patients with lung cancer

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INTRODUCTION

Around 1953, lung cancer became the most common cause of cancer deaths in men, and in 1985, it became the leading cause of cancer deaths in women. However, lung cancer deaths have begun to decline in both men and women, reflecting a decrease in smoking. (See "Females and lung cancer" .)

The majority of patients with lung cancer have advanced disease at clinical presentation. This may reflect the aggressive biology of the disease and the frequent absence of symptoms until locally advanced or metastatic disease is present. High-risk patients may be diagnosed while asymptomatic through screening with low-dose computed tomography.

Symptoms may result from local effects of the tumor, from regional or distant spread, or from distant effects not related to metastases (paraneoplastic syndromes). Approximately three-fourths of nonscreened patients have one or more symptoms at the time of diagnosis. One study noted that the most common symptoms at presentation were cough (55 percent), dyspnea (45 percent), pain (38 percent), and weight loss (36 percent) ( table 1 ) [ 3 ].

This discussion will present the clinical manifestations of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Screening and risk factors for lung cancer, as well as an overview of the initial evaluation, diagnosis, treatment, and prognosis of lung cancer are presented separately. A more detailed discussion on risk factors is also presented elsewhere.

JEFFREY KIM, MD, HOBART LEE, MD, AND BRIAN W. HUANG, MD

Am Fam Physician. 2022;105(5):487-494

Patient information: See related handout on lung cancer , written by the authors of this article.

Published online April 1, 2022.

Author disclosure: No relevant financial relationships.

Lung cancer is the second most common cancer in men and women in the United States; however, it remains the leading cause of cancer-related death in the United States and worldwide. The most common but nonspecific symptom of lung cancer is cough. Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer. Referral to a multidisciplinary lung cancer team, imaging, and confirmation through sputum cytology, thoracentesis, fine-needle aspiration, or mediastinoscopy are recommended. If lung cancer is confirmed, treatment options vary based on staging, histology, immunotherapy biomarker testing, and patient health status. Treatments include surgical resection, immunotherapy, chemotherapy, and/or radiotherapy. Family physicians should focus on primary prevention of lung cancer by encouraging tobacco cessation and early recognition by screening at-risk individuals and following guidelines for pulmonary nodules. As of 2021, the U.S. Preventive Services Task Force recommends annual lung cancer screening using low-dose computed tomography starting at 50 years of age in patients with a 20 pack-year history.

Lung cancer remains the leading cause of cancer-related death in the United States and worldwide; in the United States, it is the second most common cancer among men and women. 1 , 2 The majority of lung cancers are divided into two histologic types: non–small cell lung cancer (NSCLC; 84%) and small cell lung cancer (SCLC; 13%), which helps guide treatment. 3 Smoking is closely linked to 80% to 90% of lung cancer deaths, whereas radon exposure is a leading cause of nonsmoking-related lung cancer. 4 Several guidelines address the management of lung cancer, with the goal of improving patient outcomes. 5 In the United Kingdom, the National Institute for Health and Care Excellence has developed clinical pathways that were last updated in 2019, whereas in the United States, the most recent comprehensive lung cancer guideline from the American College of Chest Physicians was last updated in 2013, with more recent treatment recommendations from the National Comprehensive Cancer Network. 2 , 6 – 8

Clinical Presentation and Diagnosis

In-office evaluation.

When evaluating a patient for lung cancer, a detailed history and physical examination should be performed, including environmental and work exposures. Current smoking or history of smoking is the single most important risk factor for all types of lung cancer. 9 , 10 Concomitant chronic lung disease or exposure to radon or asbestos may increase the risk of lung cancer. 10

Patients with lung cancer typically present with symptoms, 11 the most common of which is cough. 9 , 11 Hemoptysis in combination with weight loss, loss of appetite, or shortness of breath increases the likelihood of lung cancer. 11 Table 1 provides signs and symptoms of lung cancer due to local effects, 12 and Table 2 and Table 3 show, respectively, advanced disease–displaying symptoms of distant metastases and paraneoplastic syndromes associated with lung cancer. 12

The initial evaluation for patients with a suspicion for lung cancer begins with laboratory testing, including a complete blood count, serum chemistries, calcium levels, and liver function tests, with chest radiography. 2 , 9 A normal chest radiograph alone should not be used to rule out lung cancer because just under 20% to 25% of normal chest radiographs may miss the disease. 13 , 14 Patients who have a high level of suspicion for lung cancer based on clinical assessment or initial chest radiography findings should receive computed tomography (CT) of the chest with intravenous contrast media, ideally to include the liver and adrenals. 2 , 15

PULMONARY NODULE FOLLOW-UP

Among patients presenting with incidental nodules found on radiographic imaging, follow-up for those older than 35 years is assessed based on features and risk categorization, as recommended by the Fleischner Society, updated in 2017 ( Table 4 ) . 16 , 17 New studies are emerging on the use of genomic classifiers and artificial intelligence to help facilitate clinical management of incidental nodules. 18 , 19 For patients meeting high-risk criteria and undergoing lung cancer screening, appropriate follow-up recommendations should be determined by the 2019 Lung-RADS guidelines 20 ( eTable A ) .

Diagnosis Confirmation

Patients with suspected lung cancer should be referred to a pulmonologist within a multidisciplinary thoracic oncology team to help guide workup. 6 Confirmation of the diagnosis should be made by one or more of the following methods, with further testing if suspicion is high and findings are negative: sputum cytology, thoracentesis of pleural fluid, bronchoscopy (often with endobronchial ultrasonography and/or electromagnetic navigation with or without fine-needle aspiration), or mediastinoscopy depending on local availability and expertise. 21

Staging of lung cancer follows the eighth edition of the American Joint Committee on Cancer's staging manual. 22 Staging revisions from the seventh edition were based on analysis of a database of 94,708 cases by the International Association for the Study of Lung Cancer Staging from 1999 to 2010. 23 The tumor, node, metastasis (TNM) classification describes the anatomic extent of the disease, is based on clinical and pathologic staging, and guides eventual treatment and prognosis 22 ( eTable B ) . Clinical TNM is based on history and physical examination findings, imaging, and staging procedures, and a pathologic TNM based on postsurgical histopathologic classification. The composite of these composes the TNM stage with associated prognostic stage groups I to IV 22 ( eTable C ) . TNM staging is recommended for NSCLC and SCLC for prognostic and tumor stratification purposes. 22 For NSCLC, brain imaging should be performed in stage IIA patients with consideration for stage IB patients; patients with stages III to IV disease should have magnetic resonance imaging of the brain to assess for metastases even in the absence of clinical disease. 7 , 24 Patients with any stage of SCLC should have brain imaging performed, preferably using magnetic resonance imaging. 8 In patients who may undergo curative treatment, positron emission tomography CT should be performed to assess intrathoracic lymph node involvement and guide subsequent sampling. 2 , 10

NON–SMALL CELL LUNG CANCER

The treatment of NSCLC varies based on staging, nonsquamous (usually adenocarcinoma) vs. squamous histology, and genetic and immunotherapy biomarker testing. Treatment options presented here provide an overview; however, specific regimens will vary based on the availability of treatment options and clinical experience of the multidisciplinary treatment team. Patients with advanced disease should be offered early palliative care. 7

Patients with stages I to II NSCLC are usually offered a combination of three treatments: surgery, which can include complete resection of the tumor (usually stages I and II), and mediastinal lymph node dissection or lymph node sampling; radiotherapy; and adjuvant platinum-based chemotherapy. 25 Select patients who have stage III NSCLC but do not have disease progression after chemotherapy may benefit from immunotherapy. 7 , 26 Video-assisted thoracic surgery has lower mortality and hospital length of stay compared with open thoracotomy. 27 Nonsurgical candidates can be offered radiotherapy and platinum-based chemotherapy. 28 For patients with stage IV disease, palliative care and immunotherapy with or without platinum-based chemotherapy are recommended. 7 In patients with fewer than three brain metastases, stereotactic radiotherapy or surgery with stereotactic radiotherapy is recommended. 29 With more than three brain metastases, whole brain radiation is recommended, although it may not improve neurocognitive symptoms or overall survival. 28 , 29 Radiotherapy and bisphosphonates are recommended for bone metastases to reduce pain and risk of skeletal fractures. 28 , 29

All patients who have NSCLC with nonsquamous NSCLC, mixed histology, or small-volume biopsies should be offered genetic and immunotherapy testing (e.g., broad-based, next-generation sequencing). 7 Common driver mutations, preferred treatment options, and common adverse effects are listed in eTable D . Genetic testing can predict overall prognosis and responsiveness to targeted therapies; however, U.S. Food and Drug Administration–approved therapies depend on histologic subtype, disease progression, and timing with first-line systemic chemo-therapy. 7 Standard first-line therapy for advanced NSCLC is immunotherapy with or without chemotherapy, based on PD-L1 (programmed death-ligand 1) status of expression on tumor cells. 7

PD-L1 expression (listed as a percentage between 0 and 100) of 50% or more can change the recommended immunotherapy regimen 7 , 29 , 30 ( eTable E ) .

In 2017, five-year survival for localized NSCLC was 59%, with only 5.8% for five-year survival in patients with distant metastases; however, there have been reductions in mortality since 2013 likely due to a decrease in incidence and advancements in therapies, as described previously 31 ( Table 5 22 ) .

SMALL CELL LUNG CANCER

For patients with limited-stage SCLC, the standard of care is etoposide (Etopophos) plus cisplatin chemotherapy and concurrent thoracic radiotherapy, with surgical resection offered in select patients. 8 , 32 Patients with significant comorbidities, including chronic kidney disease, may be offered an alternative carboplatin (Paraplatin)–based chemotherapy regimen with similar effectiveness. 32 For patients with extensive-stage SCLC, four to six cycles of one of several combination chemotherapy/immunotherapy regimens should be offered with maintenance immunotherapy. 8 Consolidative thoracic radiation may be considered for select patients with residual intrathoracic disease who have responded to systemic chemotherapy. 8 In patients with limited-stage SCLC, prophylactic cranial irradiation for brain metastases reduces mortality. 33 Localized palliative radiation for nonpulmonary sites, including whole brain radiotherapy for brain metastases, should be offered. 28 Patients with relapse after initial therapy have overall poor prognosis; however, several second-line systemic therapy options are available. 8 , 34 Prognosis remains poor, with only 20% to 25% five-year survival for limited-stage SCLC and less than 10% two-year survival for extensive-stage SCLC 35 ( Table 5 22 ) .

As of 2021, the U.S. Preventive Services Task Force (USPSTF) has recommended annual low-dose CT screening in adults 50 to 80 years of age who have a 20 pack-year smoking history and currently smoke or have quit smoking within the past 15 years. 36 This replaces the 2013 recommendation of annual CT screenings for patients 55 to 80 years of age with at least a 30 pack-year history. 37 The criteria for discontinuing screening are unchanged, including patients who have quit smoking for more than 15 years, have limited life expectancies (less than 10 years), or are not willing to undergo curative lung surgery. 36

The updated recommendation is based on two major randomized controlled trials, the National Lung Screening Trial and the Dutch–Belgian lung-cancer screening trial (Nederlands–Leuvens Longkanker Screenings Onderzoek). 38 , 39 Both of these trials found reductions in lung cancer mortality, with a number needed to screen to prevent one lung cancer death of 323 over 6.5 years of follow-up and 130 over 10 years of follow-up, respectively. 38 – 40 Through systematic review of these trials and modeling studies from the Cancer Intervention and Surveillance Modeling Network, the USPSTF updated its criteria for screening. 36 Earlier screening recommendations are based on studies that suggest this may help address screening disparities for certain populations, including women and Black and Hispanic people. 41 , 42 Compared with the previous USPSTF 2013 guideline, Cancer Intervention and Surveillance Modeling Network data suggest that earlier screenings would be associated with an increase in the reduction of lung cancer mortality, from a 9.8% reduction to 12.1% to 14.4%, and life-years gained, from 4,882 life-years to 6,018 to 7,596 per 100,000. 37 , 43 The American Academy of Family Physicians supports the USPSTF's grade B recommendation of lung cancer screening in adults at increased risk; however, the harms of annual CT screenings are still not well documented, and further research is needed. 44 Research gaps include evaluating potential harms associated with increased radiation exposure, identifying better technology to differentiate benign and malignant lung nodules to avoid overdiagnosis, and addressing the cost and availability of increased screening in economically disadvantaged populations. 44

Smoking Cessation and Counseling

Smoking cessation reduces morbidity and mortality in patients with lung cancer ; however, no randomized controlled trials have compared specific cessation interventions in this population. 29 , 45 Exercise training may improve exercise capacity and quality of life. 46 Nursing interventions can help patients with dyspnea, and a range of psychological interventions may improve coping skills and quality of life. 47

Although all actively smoking patients should be offered cessation support, lung cancer screening for eligible patients coupled with cessation support may be associated with higher quitting rates. 48 This combination is believed to serve as a teachable moment during a time when patients are the most receptive to quitting advice. Cessation assistance in combination with CT screening has been associated with a reduction in lung cancer–specific mortality and the potential to improve the cost-effectiveness ratio of screening. 49 , 50 Patients who quit smoking have been shown to reduce their risk of lung cancer by 39.1% after five years. 51 Patients should also be counseled that quitting smoking will reduce their risk of all second cancers by 3.5 times. 52

This article updates previous articles on this topic by Latimer and Mott 12 and Collins, et al. 53

Data Sources: A PubMed search was completed in Clinical Queries using the key terms lung cancer, diagnosis, treatment, and screening. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. The Agency for Healthcare Research and Quality Effective Healthcare Reports, the U.S. Preventive Services Task Force, the Cochrane Database of Systematic Reviews, DynaMed, Essential Evidence Plus, the National Institute for Health and Care Excellence, and the National Comprehensive Cancer Network were also searched. Search dates: April and May 2021, and January 28, 2022.

The authors thank Hamid Mirshahidi, MD, associate professor of medicine, hematology and oncology, and Laren Tan, MD, associate professor of medicine, pulmonary and critical care, Loma Linda University School of Medicine, for thoughtful advice and review of the manuscript.

Centers for Disease Control and Prevention. United States cancer statistics: data visualizations; June 2021. Accessed January 28, 2022. www.cdc.gov/cancer/dataviz

• Maconachie R, Mercer T, Navani N, et al.; Guideline Committee. Lung cancer: diagnosis and management: summary of updated NICE guidance [published correction appears in BMJ . 2019;365:I1514]. BMJ. 2019;364:l1049.

American Cancer Society. Cancer facts & figures; 2021. Accessed October 13, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf

Centers for Disease Control and Prevention. What are the risk factors for lung cancer? Accessed October 2021. https://www.cdc.gov/cancer/lung/basic_info/risk_factors.htm

• Wilshire CL, Rayburn JR, Chang SC, et al. Not following the rules in guideline care for lung cancer diagnosis and staging has negative impact. Ann Thorac Surg. 2020;110(5):1730-1738.
• Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):7S-37S.

National Comprehensive Cancer Network. Non-small cell lung cancer (version 04.2021). Accessed May 7, 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

National Comprehensive Cancer Network. Small cell lung cancer (version 03.2021). Accessed May 5, 2021. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf

• Ost DE, Yeung S-CJ, Tanoue LT, et al. Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e121S-e141S.
• Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e1S-e29S.
• Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made? A population based case-control study. Thorax. 2005;60(12):1059-1065.

Latimer KM, Mott TF. Lung cancer: diagnosis, treatment principles, and screening. Am Fam Physician. 2015;91(4):250-256. Accessed December 17, 2021. https://www.aafp.org/afp/2015/0215/p250.html

• Foley RW, Nassour V, Oliver HC, et al. Chest x-ray in suspected lung cancer is harmful. Eur Radiol. 2021;31(8):6269-6274.

Dwyer-Hemmings L, Fairhead C. The diagnostic performance of chest radiographs for lung malignancy in symptomatic primary-care populations: a systematic review and meta-analysis. BJR Open. 2021;3(1):20210005.

National Institute for Health and Care Excellence. Lung cancer: diagnosis and management. NICE guideline [NG122]; March 28, 2019. Accessed December 22, 2021. https://www.nice.org.uk/guidance/ng122/chapter/Recommendations

• MacMahon H, Naidich DP, Goo JM, et al. Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology. 2017;284(1):228-243.
• Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e93S-e120S.
• Lee HJ, Mazzone P, Feller-Kopman D, et al.; Percepta Registry Investigators. Impact of the Percepta genomic classifier on clinical management decisions in a multicenter prospective study. Chest. 2021;159(1):401-412.
• Massion PP, Antic S, Ather S, et al. Assessing the accuracy of a deep learning method to risk stratify indeterminate pulmonary nodules. Am J Respir Crit Care Med. 2020;202(2):241-249.

American College of Radiology. Lung-RADS version 1.1; 2019. Accessed May 18, 2021. https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/LungRADSAssessmentCategoriesv1-1.pdf

Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e142S-e165S.

• Detterbeck FC, Boffa DJ, Kim AW, et al. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193-203.
• Goldstraw P, Chansky K, Crowley J, et al.; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39-51.
• Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e211S-e250S.
• Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e278S-e313S.
• Antonia SJ, Villegas A, Daniel D, et al.; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.

Nakamura H. Systematic review of published studies on safety and efficacy of thoracoscopic and robot-assisted lobectomy for lung cancer. Ann Thorac Cardiovasc Surg. 2014;20(2):93-98.

• Tsao MN, Xu W, Wong RKS, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018;(1):CD003869.
• Planchard D, Popat S, Kerr K, et al.; ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol . 2019; 30(5): 863–870]. Ann Oncol. 2018;29(suppl 4):iv192-iv237.
• Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al.; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
• Howlader N, Noone AM, Krapcho M, et al. National Cancer Institute. SEER cancer statistics review (CSR), 1975–2017; April 15, 2020. Accessed January 28, 2022. https://seer.cancer.gov/csr/1975_2017
• Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30(14):1692-1698.
• Aupérin A, Arriagada R, Pignon JP, et al.; Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1999;341(7):476-484.
• Eckardt JR, von Pawel J, Pujol J-L, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer [published correction appears in J Clin Oncol . 2007;25(22):3387]. J Clin Oncol. 2007;25(15):2086-2092.
• Jett JR, Schild SE, Kesler KA, et al. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e400S-e419S.
• Krist AH, Davidson KW, Mangione CM, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970.

Moyer VA. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(5):330-338.

• Aberle DR, Adams AM, Berg CD, et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
• de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513.
• Jonas DE, Reuland DS, Reddy SM, et al. Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987.
• Aldrich MC, Mercaldo SF, Sandler KL, et al. Evaluation of USPSTF lung cancer screening guidelines among African American adult smokers [published correction appears in JAMA Oncol . 2019;5(9):1372]. JAMA Oncol. 2019;5(9):1318-1324.

Pinsky PF, Kramer BS. Lung cancer risk and demographic characteristics of current 20–29 pack-year smokers: implications for screening. J Natl Cancer Inst. 2015;107(11):djv226.

Meza R, Jeon J, Toumazis I, et al. Evaluation of the benefits and harms of lung cancer screening with low-dose computed tomography: a collaborative modeling study for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality; 2021. AHRQ publication 20-05266-EF-2.

American Academy of Family Physicians. Clinical preventive service recommendation. Lung cancer screening, adult. Accessed April 25, 2021. https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/lung-cancer.html

• Zeng L, Yu X, Yu T, et al. Interventions for smoking cessation in people diagnosed with lung cancer. Cochrane Database Syst Rev. 2019;(6):CD011751.
• Peddle-McIntyre CJ, Singh F, Thomas R, et al. Exercise training for advanced lung cancer. Cochrane Database Syst Rev. 2019;(2):CD012685.
• Rueda J-R, Solà I, Pascual A, et al. Non-invasive interventions for improving well-being and quality of life in patients with lung cancer. Cochrane Database Syst Rev. 2011;(9):CD004282.
• Pistelli F, Aquilini F, Falaschi F, et al.; ITALUNG Working Group. Smoking cessation in the ITALUNG lung cancer screening: what does “teachable moment” mean?  Nicotine Tob Res. 2020;22(9):1484-1491.
• Tanner NT, Kanodra NM, Gebregziabher M, et al. The association between smoking abstinence and mortality in the National Lung Screening Trial. Am J Respir Crit Care Med. 2016;193(5):534-541.
• Goffin JR, Flanagan WM, Miller AB, et al. Biennial lung cancer screening in Canada with smoking cessation-outcomes and cost-effectiveness. Lung Cancer. 2016;101:98-103.
• Tindle HA, Stevenson Duncan M, Greevy RA, et al. Lifetime smoking history and risk of lung cancer: results from the Framingham Heart Study [published correction appears in J Natl Cancer Inst . 2018;110(10):1153]. J Natl Cancer Inst. 2018;110(11):1201-1207.
• Leone FT, Evers-Casey S, Toll BA, et al. Treatment of tobacco use in lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e61S-e77S.
• Collins LG, Haines C, Perkel R, et al. Lung cancer: diagnosis and management. Am Fam Physician. 2007;75(1):56-63. Accessed December 22, 2021. https://www.aafp.org/afp/2007/0101/p56.html

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• Patient Care & Health Information
• Diseases & Conditions
• Lung cancer

Lung cancer begins in the cells of the lungs.

Lung cancer is a kind of cancer that starts as a growth of cells in the lungs. The lungs are two spongy organs in the chest that control breathing.

Lung cancer is the leading cause of cancer deaths worldwide.

People who smoke have the greatest risk of lung cancer. The risk of lung cancer increases with the length of time and number of cigarettes smoked. Quitting smoking, even after smoking for many years, significantly lowers the chances of developing lung cancer. Lung cancer also can happen in people who have never smoked.

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Lung cancer typically doesn't cause symptoms early on. Symptoms of lung cancer usually happen when the disease is advanced.

Signs and symptoms of lung cancer that happen in and around the lungs may include:

• A new cough that doesn't go away.
• Chest pain.
• Coughing up blood, even a small amount.
• Hoarseness.
• Shortness of breath.

Signs and symptoms that happen when lung cancer spreads to other parts of the body may include:

• Losing weight without trying.
• Loss of appetite.
• Swelling in the face or neck.

When to see a doctor

Make an appointment with your doctor or other healthcare professional if you have any symptoms that worry you.

If you smoke and haven't been able to quit, make an appointment. Your healthcare professional can recommend strategies for quitting smoking. These may include counseling, medicines and nicotine replacement products.

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Lung cancer happens when cells in the lungs develop changes in their DNA. A cell's DNA holds the instructions that tell a cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells.

The cancer cells might form a mass called a tumor. The tumor can grow to invade and destroy healthy body tissue. In time, cancer cells can break away and spread to other parts of the body. When cancer spreads, it's called metastatic cancer.

Smoking causes most lung cancers. It can cause lung cancer in both people who smoke and in people exposed to secondhand smoke. But lung cancer also happens in people who never smoked or been exposed to secondhand smoke. In these people, there may be no clear cause of lung cancer.

How smoking causes lung cancer

Researchers believe smoking causes lung cancer by damaging the cells that line the lungs. Cigarette smoke is full of cancer-causing substances, called carcinogens. When you inhale cigarette smoke, the carcinogens cause changes in the lung tissue almost immediately.

At first your body may be able to repair this damage. But with each repeated exposure, healthy cells that line your lungs become more damaged. Over time, the damage causes cells to change and eventually cancer may develop.

Types of lung cancer

Lung cancer is divided into two major types based on the appearance of the cells under a microscope. Your healthcare professional makes treatment decisions based on which major type of lung cancer you have.

The two general types of lung cancer include:

• Small cell lung cancer. Small cell lung cancer usually only happens in people who have smoked heavily for years. Small cell lung cancer is less common than non-small cell lung cancer.
• Non-small cell lung cancer. Non-small cell lung cancer is a category that includes several types of lung cancers. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Risk factors

A number of factors may increase the risk of lung cancer. Some risk factors can be controlled, for instance, by quitting smoking. Other factors can't be controlled, such as your family history.

Risk factors for lung cancer include:

Your risk of lung cancer increases with the number of cigarettes you smoke each day. Your risk also increases with the number of years you have smoked. Quitting at any age can significantly lower your risk of developing lung cancer.

Exposure to secondhand smoke

Even if you don't smoke, your risk of lung cancer increases if you're around people who are smoking. Breathing the smoke in the air from other people who are smoking is called secondhand smoke.

Previous radiation therapy

If you've had radiation therapy to the chest for another type of cancer, you may have an increased risk of developing lung cancer.

Exposure to radon gas

Radon is produced by the natural breakdown of uranium in soil, rock and water. Radon eventually becomes part of the air you breathe. Unsafe levels of radon can build up in any building, including homes.

Exposure to cancer-causing substances

Workplace exposure to cancer-causing substances, called carcinogens, can increase your risk of developing lung cancer. The risk may be higher if you smoke. Carcinogens linked to lung cancer risk include asbestos, arsenic, chromium and nickel.

Family history of lung cancer

People with a parent, sibling or child with lung cancer have an increased risk of the disease.

Complications

Lung cancer can cause complications, such as:

Shortness of breath

People with lung cancer can experience shortness of breath if cancer grows to block the major airways. Lung cancer also can cause fluid to collect around the lungs and heart. The fluid makes it harder for the affected lung to expand fully when you inhale.

Coughing up blood

Lung cancer can cause bleeding in the airway. This can cause you to cough up blood. Sometimes bleeding can become severe. Treatments are available to control bleeding.

Advanced lung cancer that spreads can cause pain. It may spread to the lining of a lung or to another area of the body, such as a bone. Tell your healthcare professional if you experience pain. Many treatments are available to control pain.

Fluid in the chest

Lung cancer can cause fluid to accumulate in the chest, called pleural effusion. The fluid collects in the space that surrounds the affected lung in the chest cavity, called the pleural space.

Pleural effusion can cause shortness of breath. Treatments are available to drain the fluid from your chest. Treatments can reduce the risk that pleural effusion will happen again.

Cancer that spreads to other parts of the body

Lung cancer often spreads to other parts of the body. Lung cancer may spread to the brain and the bones.

Cancer that spreads can cause pain, nausea, headaches or other symptoms depending on what organ is affected. Once lung cancer has spread beyond the lungs, it's generally not curable. Treatments are available to decrease symptoms and to help you live longer.

There's no sure way to prevent lung cancer, but you can reduce your risk if you:

Don't smoke

If you've never smoked, don't start. Talk to your children about not smoking so that they can understand how to avoid this major risk factor for lung cancer. Begin conversations about the dangers of smoking with your children early so that they know how to react to peer pressure.

Stop smoking

Stop smoking now. Quitting reduces your risk of lung cancer, even if you've smoked for years. Talk to your healthcare team about strategies and aids that can help you quit. Options include nicotine replacement products, medicines and support groups.

Avoid secondhand smoke

If you live or work with a person who smokes, urge them to quit. At the very least, ask them to smoke outside. Avoid areas where people smoke, such as bars. Seek out smoke-free options.

Test your home for radon

Have the radon levels in your home checked, especially if you live in an area where radon is known to be a problem. High radon levels can be fixed to make your home safer. Radon test kits are often sold at hardware stores and can be purchased online. For more information on radon testing, contact your local department of public health.

Avoid carcinogens at work

Take precautions to protect yourself from exposure to toxic chemicals at work. Follow your employer's precautions. For instance, if you're given a face mask for protection, always wear it. Ask your healthcare professional what more you can do to protect yourself at work. Your risk of lung damage from workplace carcinogens increases if you smoke.

Eat a diet full of fruits and vegetables

Choose a healthy diet with a variety of fruits and vegetables. Food sources of vitamins and nutrients are best. Avoid taking large doses of vitamins in pill form, as they may be harmful. For instance, researchers hoping to reduce the risk of lung cancer in people who smoked heavily gave them beta carotene supplements. Results showed the supplements increased the risk of cancer in people who smoke.

Exercise most days of the week

If you don't exercise regularly, start out slowly. Try to exercise most days of the week.

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• Non-small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450. Accessed Dec. 4, 2023.
• Small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462. Accessed Dec. 4, 2023.
• Niederhuber JE, et al., eds. Cancer of the lung: Non-small cell lung cancer and small cell lung cancer. In: Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 4, 2023.
• Non-small cell lung cancer treatment (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Accessed Dec. 4, 2023.
• Small cell lung cancer treatment (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/lung/patient/small-cell-lung-treatment-pdq. Accessed Dec. 4, 2023.
• Lung cancer – non-small cell. Cancer.Net. https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed Dec. 4, 2023.
• Lung cancer – small cell. Cancer.Net. https://www.cancer.net/cancer-types/33776/view-all. Accessed Dec. 4, 2023.
• Detterbeck FC, et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.1378/chest.12-2377.
• Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Dec. 4, 2023.
• Lung cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/lung-cancer. Accessed Dec. 4, 2023.
• Cairns LM. Managing breathlessness in patients with lung cancer. Nursing Standard. 2012; doi:10.7748/ns2012.11.27.13.44.c9450.
• Warner KJ. Allscripts EPSi. Mayo Clinic. Jan. 13, 2020.
• Brown AY. Allscripts EPSi. Mayo Clinic. July 30, 2019.
• Searching for cancer centers. American College of Surgeons. https://www.facs.org/search/cancer-programs. Accessed Dec. 4, 2023.
• Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. New England Journal of Medicine. 2010; doi:10.1056/NEJMoa1000678.
• Dunning J, et al. Microlobectomy: A novel form of endoscopic lobectomy. Innovations. 2017; doi:10.1097/IMI.0000000000000394.
• Leventakos K, et al. Advances in the treatment of non-small cell lung cancer: Focus on nivolumab, pembrolizumab and atezolizumab. BioDrugs. 2016; doi:10.1007/s40259-016-0187-0.
• Dong H, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;5:1365.
• Aberle DR, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011; doi:10.1056/NEJMoa1102873.
• Infographic: Lung Cancer
• Lung cancer surgery
• Lung nodules: Can they be cancerous?
• Super Survivor Conquers Cancer

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• Review Article
• Open access
• Published: 18 October 2022

A systematic review of interventions to recognise, refer and diagnose patients with lung cancer symptoms

• Mohamad M. Saab   ORCID: orcid.org/0000-0002-7277-6268 1 ,
• Megan McCarthy 1 ,
• Michelle O’Driscoll 1 ,
• Laura J. Sahm 2 ,
• Patricia Leahy-Warren 1 ,
• Brendan Noonan 1 ,
• Serena FitzGerald 1 ,
• Maria O’Malley 1 ,
• Noreen Lyons 3 ,
• Heather E. Burns 4 ,
• Una Kennedy 4 ,
• Áine Lyng 4 &
• Josephine Hegarty 1  

npj Primary Care Respiratory Medicine volume  32 , Article number:  42 ( 2022 ) Cite this article

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• Respiratory signs and symptoms
• Respiratory tract diseases

Patients with lung cancer (LC) often experience delay between symptom onset and treatment. Primary healthcare professionals (HCPs) can help facilitate early diagnosis of LC through recognising early signs and symptoms and making appropriate referrals. This systematic review describes the effect of interventions aimed at helping HCPs recognise and refer individuals with symptoms suggestive of LC. Seven studies were synthesised narratively. Outcomes were categorised into: Diagnostic intervals; referral and diagnosis patterns; stage distribution at diagnosis; and time interval from diagnosis to treatment. Rapid access pathways and continuing medical education for general practitioners can help reduce LC diagnostic and treatment delay. Awareness campaigns and HCP education can help inform primary HCPs about referral pathways. However, campaigns did not significantly impact LC referral rates or reduce diagnostic intervals. Disease outcomes, such as LC stage at diagnosis, recurrence, and survival were seldom measured. Review findings highlight the need for longitudinal, powered, and controlled studies.

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Introduction

Lung cancer (LC) is the most common cause of cancer incidence and mortality worldwide, with 2.1 million new cases and 1.8 million deaths in 2018 1 . It is estimated that, by 2040, the number of annual LC diagnoses and deaths will increase to 3.63 and 3.01 million respectively 2 . Worldwide, more than half of LCs (53%) are diagnosed in people aged between 55 and 74 years 3 . Data from 185 countries indicate that LC is typically diagnosed at an advanced stage, with a 5-year survival rate of 10–20% 4 .

LC has a relatively broad symptom signature compared to other cancers, such as breast and testicular cancers that typically present with a single identifiable symptom (e.g., painless lump) 5 , 6 , 7 . Early-stage LC can be asymptomatic or can cause a range of symptoms including a persistent cough, changes to an existing cough, shortness of breath, and chest pain 8 , 9 . Systemic symptoms, such as unexplained weight loss and fatigue, are typically associated with advanced disease 10 . Haemoptysis is one of the strongest symptom predictors of LC 8 , 11 . The broad symptom signature of LC, and overlap with common symptoms of benign disease, may contribute to delays in presentation and diagnosis 12 .

Early medical help-seeking for symptoms suggestive of LC is a key enabler of early diagnosis, curative treatment, and improved survival 11 . However, a Swedish study found that patients diagnosed with LC experience, on average, a 6-month delay between symptom onset and initiation of treatment 13 . Reasons for delayed patient help-seeking include patient factors, such as symptom misappraisal, fear of a potential cancer diagnosis, and guilt associated with smoking 14 , 15 , as well as healthcare system factors, such as the high financial cost of healthcare, lack of access to healthcare, and previous bad experiences with the healthcare system 15 , 16 , 17 , 18 .

Primary healthcare professionals (HCPs) play a key role in facilitating early diagnosis through recognising people with signs and symptoms suggestive of LC and referring them appropriately 19 . HCP-related barriers to early diagnosis of LC may include lack of awareness of signs and symptoms of LC, inadequate access to diagnostics and rapid referral pathways, and fear of overburdening the healthcare system 15 , 18 . In this systematic review, we identify and describe the effect of interventions aimed at helping HCPs recognise and refer individuals with signs and symptoms indicative of LC to the appropriate healthcare pathway in a timely manner.

This systematic review was guided by the Cochrane Handbook for Systematic Reviews of Interventions 20 and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 21 (Supplementary Table 1 ).

Eligibility criteria

Using a modified version of the population, intervention, comparison, and outcomes (PICO) framework 22 , to include “S” for study design and “T” for timeframe (PICOST), the systematic review inclusion criteria were as follows: population: any HCPs. Studies were included only when patient outcomes were reported as a result of an intervention targeted towards HCPs; Intervention: any intervention, campaign, programme, trial, education, algorithm, decision tree/support, or guide aimed at improving early diagnosis of symptomatic LC; comparison: any pre-post comparison; outcomes: any outcomes (e.g., LC diagnosis among symptomatic patients, stage of LC at diagnosis, LC treatments received, and LC survival); study design: any experimental design; and timeframe: studies published between January 2011 and September 2021 in order to identify the latest evidence.

Studies were excluded if interventions were exclusively targeted at patients, did not incorporate a comparator, and/or used non-experimental designs. Studies focusing on detection of LC in asymptomatic individuals (i.e., through screening or surveillance) were also excluded. Moreover, we excluded conference proceedings, dissertations, and theses.

Search strategy

MEDLINE, CINAHL, ERIC, and Academic Search Complete were searched on September 13, 2021. Truncation “*” was used and keywords were combined using Boolean operators “OR” and “AND” and the proximity indicator “N.” The following keywords were searched based on title or abstract: (Interven* OR program* OR campaign* OR trial* OR experiment* OR educat* OR algorithm* OR “decision* tree*” OR “decision* support*” OR guid*) AND (Refer* OR consult* OR recogni* OR counsel* OR advice OR advis* OR detect* OR find* OR triag* OR direct* OR manag* OR signpost* OR know* OR aware* OR understand*) AND ((Lung* OR pulmo*) N3 (cancer* OR neoplas* OR malignan* OR tumo* OR symptom* OR sign*)) AND (“Health* profession*” OR “health care profession*” OR HCP* OR “health* work*” OR “health care work*” OR HCW* OR clinician* OR nurs* OR “public health nurs*” OR PHN* OR “community nurs*” OR “clinic nurs*” OR “practice nurs*” OR pharmac* OR chemist* OR doctor* OR physician* OR “general practitioner*” OR GP* OR consultant*).

Study extraction and synthesis

Records were screened in Covidence, an online software used to streamline the production of systematic reviews 23 . First, titles and abstracts were screened, and irrelevant records were excluded. Full texts of potentially eligible records were then sourced and screened. Each record was title, abstract, and full text screened twice by two independent reviewers. Screening conflicts were resolved by a third reviewer.

The following data were extracted for each study using a standardised table 14 , 24 (Supplementary Table 2 ): author(s); year; country; aim; design; theoretical underpinning; sample; setting; relevant outcomes; intervention; procedures; instruments; follow-up time(s); and relevant findings. One reviewer conducted data extraction. Each extracted study was then cross-checked for accuracy by the review team. Meta-analyses were not plausible due to significant heterogeneity in study design, interventions, and outcome measures. Instead, a narrative synthesis was conducted, which involved grouping and synthesising the results according to the outcomes measured within the reviewed studies 25 .

Quality appraisal and level of evidence assessment

The Mixed Methods Appraisal Tool was used to appraise the methodological quality of the included randomised controlled trials (RCTs) and non-RCTs 26 . Quality appraisal was conducted in terms of the appropriateness of recruitment, data collection, and data analysis to the research question. Each item was voted on a “yes,” “no,” and “cannot tell” basis. The Scottish Intercollegiate Guidelines Network 27 grading system was used to assess the level of evidence for each of the included studies. The eight levels of evidence range between 1++, 1+, 1−, 2++, 2+, 2−, 3, and 4. For instance, a score of 1++ corresponds to high quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias, whereas a score of 4 is assigned to expert opinions 27 . Quality appraisal and level of evidence assessment were conducted by one reviewer and cross-checked for correctness by the review team.

Study selection

Database searching resulted in 5829 records. Following deletion of duplicates, 3556 records were screened by title and abstract and 3458 irrelevant records were excluded. The full texts of the remaining 98 records were obtained and screened. Of those, seven were included in this systematic review (Fig. 1 ).

Study identification, screening, and selection process.

Study characteristics

Most of the studies were conducted in Denmark ( n  = 2) and England ( n  = 2) and were non-RCTs ( n  = 5). Sample size ranged widely between 72 28 and 56,020 29 participants and follow-up times varied from 3 30 to 37 months 31 . Five different interventions were used across the seven studies, including: (i) Combined public and HCP LC awareness campaigns; 30 , 32 (ii) letters and continuing medical education (CME) meetings to educate general practitioners (GPs) about referral criteria for fast-track evaluation of patients with “reasonable suspicion” of LC (maximum 72 h waiting time for evaluation, which includes low dose computed tomography [LDCT]); 33 , 34 (iii) a cancer fast-track programme (i.e., target of 30 days between well-founded suspicion of cancer by a GP and the start of treatment). Referrals to this programme can also originate from emergency departments or other clinical departments involved in routine monitoring or screening; 29 (iv) the thoracic-trained advanced practice provider-led LC strategist programme to minimise diagnostic redundancy, streamline management decisions for indeterminate nodules, and expedite curative therapy. Once patients were referred from primary care to secondary care, an individual evaluation strategy was developed and followed for them; 31 and (v) multi-disciplinary meetings, screensavers, and posters to reduce delay between initial suspicion of LC and measurement of serum calcium levels 28 . Of note, Hypercalcaemia is a serious complication of LC and is associated with poorer prognosis 28 . The full characteristics of the included studies are presented in Table 1 .

All the included non-RCTs ( n  = 5) used appropriate data collection methods, outcome measures, and intervention administration. Outcome data were complete in all non-RCTs. Four non-RCTs had clear research questions. The study by Philips et al. 31 did not have a clear aim statement, despite clearly stated hypotheses. Only one non-RCT reported that participants were representative of the target population 33 and only one non-RCT reported that confounders were accounted for in the study design 28 . Both RCTs ( n  = 2) had clear research aims, performed randomisation appropriately, collected data in line with the research aims, had groups that were comparable at baseline, and reported on participant adherence to the assigned intervention 30 , 34 . However, the outcome assessor was not blinded in Gudlbrant et al.’s 34 RCT.

Four studies scored 2+ on the Scottish Intercollegiate Guidelines Network 27 level of evidence criteria, indicating well-conducted non-RCTs with a low risk of confounding or bias and a moderate probability that the relationship is causal 29 , 31 , 32 , 33 . Only one study scored 2++, indicating a well-conducted non-RCT with a low risk of confounding or bias and a moderate probability that the relationship is causal 28 . Both RCTs scored 1+ indicating well-conducted RCTs with a low risk of bias 30 , 34 . See Table 2 for quality and level of evidence assessment.

Synthesis of findings

Outcomes reported in the reviewed studies were categorised into four categories as follows: diagnostic intervals; referral and diagnosis patterns; stage distribution at diagnosis; and time interval from diagnosis to treatment.

Diagnostic interval

Four studies aimed to reduce the diagnostic interval (i.e., the time from the first presentation with symptoms of LC until diagnosis 35 ) using the LC strategist programme 31 , a community- and GP-targeted cancer awareness campaign 30 , information on LDCT and CME sessions 34 , and a multimodal quality improvement project 28 .

A retrospective review of the LC strategist programme found that time from suspicious findings on CT chest, chest X-ray, and to a lesser extent abdominal CT, to initiation of diagnostic workup of lung nodules for treatment or surveillance was significantly shorter with the programme in comparison to routine referral (3 vs 28 days respectively, p  < 0.001) 31 . Following referral, the median time to workup was also significantly shorter with the programme in comparison to routine referral (1 vs 7 days respectively, p  < 0.001) 31 .

In contrast, a concurrent community- and GP-targeted breast, prostate, colorectal, and LC awareness campaign found no statistically significant difference in the total diagnostic interval at community (i.e., public intervention) level (median total diagnostic interval = 114.5 days pre-test vs 114 days post-test, mean difference = 0.06, 95% confidence interval [CI] 0.39–0.5, p  = 0.79) or at GP level (median total diagnostic interval = 115 days pre-test vs 125 days post-test, mean difference = 0.02, 95%CI 0.56–0.60, p  = 0.45) 30 . Likewise, a study measuring the effect of an intervention to inform GPs about direct access to LDCT found no statistically significant difference in primary care interval (i.e., the time from the patient’s first symptomatic presentation in primary care until referral to secondary care 35 ) between patients of GPs who received information about indications for LDCT (intervention group) (media n  = 14 days, inter quartile intervals [IQI] = 4–53) and patients of GPs who did not receive this information (control group) (media n  = 18 days, IQI = 5–69, Prevalence Ratio [PR] = 0.99, 95%CI 0.65–1.54, p  = 0.455) 34 . Moreover, no statistically significant difference was found in the diagnostic interval between patients in the intervention group (media n  = 44 days, IQI = 17–83) and the control group (media n  = 36 days, IQI = 17-112, PR = 0.8, 95%CI 0.5–1.27, p  = 0.299). However, the primary care and diagnostic intervals in the intervention group were significantly shorter if the GP also participated in a 1-h small-group-based CME session (primary care interval median = 9 days [with CME] vs 37 days [without CME], p  = 0.048; diagnostic interval median=23 days [with CME] vs 66 days [without CME], p  = 0.008) 34 .

In their quality improvement project, Apthrop et al. 28 used multidisciplinary meetings, screensavers, and posters encouraging secondary care physicians to order serum calcium levels in patients with a suspected diagnosis of LC. This project aimed to help reduce delay between initial suspicion of LC and ordering serum calcium levels during initial LC diagnostic workup in England. This project led to a statistically significant reduction in overall median time to ordering serum calcium levels in patients with a suspected diagnosis of LC, from 13 days pre-test (i.e., before the quality improvement project) to 7 days post-test ( p  = 0.001) 28 .

Referral and diagnosis patterns

Three studies reported on patterns of LC referral and diagnosis following implementation of a public awareness and GP training campaign 32 , a cancer fast-track programme 29 , and GP information and CME sessions on indications for LDCT 33 . Athey et al. 32 delivered a public and GP LC awareness campaign in six English communities with high LC incidence served by 11 GP surgeries (intervention group). This campaign ran for six weeks and used a “push-pull” approach to “push” the public to seek help for symptoms of concern and encourage GPs to “pull” symptomatic individuals into appropriate services. Five other communities served by nine GP surgeries with similar demographics served as the control group. There was a 27% increase in the number of chest X-rays ordered in the intervention group compared to a 19% increase in the control group during the campaign and six months post-test. In comparison to pre-campaign, there was a sustained increase in chest X-rays requested in the intervention group (20% relative increase) in comparison to a 2% relative reduction in the control group (Incidence Rate Ratio [IRR] = 1.22, 95%CI 1.12–1.33, p  = 0.001) at 12 months post-campaign. Moreover, LC diagnoses increased by 27% (relative increase) in the intervention group and fell by 10% (relative reduction) in the control group. However, this was not statistically significant (IRR = 1.42, 95%CI 0.83–2.44, p  = 0.199) 32 .

In a study of a cancer fast-track programme in Catalonia, Prades et al. 29 noted increased use of the programme over time, with 3336 patients with suspected LC referred via the programme in 2006, compared to 3841 patients in 2009. The proportion of all new LCs that were diagnosed through this programme fell from 60.2% (95%CI 59.8–63.4%) in 2006 to 53.2% (95%CI 51.5–54.9%) in 2009. GPs were the source of 60.6% of referrals to the fast-track programme in 2006 (95%CI 59–62.3%), falling to 41.4% (95%CI 39.7–42.9%) in 2009, demonstrating increased referrals from other sources such as hospital-based clinicians and services. The LC detection rate via the programme fell from 49.9% (95%CI 48.2–51.6%) in 2006 to 39.7% (95%CI 38.1–41.2%) in 2009. Prades et al. 29 reported a statistically significant increase in GP compliance with cancer fast-track referral guidelines from 70.8% in 2006 (95%CI 69.1–72.1%) to 82.3% in 2009 (95%CI 81.1–83.5%).

In a cohort study nested in an RCT, Guldbrandt 33 examined the use of a fast-track referral option for GPs for patients with suspected LC and the effect of GP education and awareness training on direct referral to LDCT. This education comprised a one-hour CME session and information about LDCT, including indications and Positive Predictive Values (PPV) for LC (i.e., the ratio of patients truly diagnosed as positive to all those who had positive test results). Results showed that, out of 648 patients directly referred to LDCT, absolute numbers of referrals were significantly higher (61%, 95%CI 54–66%) among GPs working in a clinic with one or more CME-participating GPs. However, the referral rate to LDCT via fast-track was 0.13 per 1000 adults per month (95%CI 0.09–0.19) for CME-participating GPs compared to 0.14 (95%CI 0.09–0.20) for non-participating GPs. The PPV for LC diagnosis due to referral to a fast-track LC pathway was 13.3% (95%CI 8.7–19.1%) for CME-participating GPs and 6.1% (95%CI 3–11%) for non-participating GPs (2.2 higher PPV). This was found to be statistically significant ( p  = 0.027) 33 .

Stage distribution at diagnosis

Three studies reported on LC stage at diagnosis following an intervention. Athey et al. 32 examined LC stage at diagnosis following a “push-pull” LC awareness campaign, Guldbrandt et al. 34 examined LC stage at diagnosis following an information programme and CME sessions on LDCT for GPs, and Philips et al. 31 examined LC stage at diagnosis following the LC strategist programme. Athey et al. 32 found no significant stage shift three months, six months, or one year following the LC “push-pull” awareness campaign. Similarly, Guldbrandt et al. 34 reported a non-statistically significant difference in stage of LC at diagnosis between the intervention group (i.e., information and CME sessions on LDCT) and control group ( p  = 0.586 for advanced LC and p  = 0.595 for localised LC). Philips et al. 31 also found non-statistically significant difference in stage at diagnosis for the seven patients in the LC strategist programme and 33 routine referral patients who underwent surgery for LC. This was the only study to report on disease free survival and overall survival. It was found that six of the seven patients (85.7%) in the LC strategist programme cohort were found to have early-stage disease with a median time of 37 days from suspicious imaging to treatment 31 . In these six patients, with a median duration of follow up of 33 months, disease free survival and overall survival were 100% (i.e., no LC recurrence and no LC death). As for the routine referral group, 25 of 33 patients (75.7%) were found to have early-stage LC with a median time of 68 days from suspicious imaging to treatment. In these 25 patients, there were six recurrences (76% disease free survival) and no deaths (100% overall survival) over a median time of 35 months. The differences in survival rates between the LC strategist programme group and the routine referral group were not statistically significant 31 .

Time interval from diagnosis to treatment

The time from LC diagnosis to treatment was measured in two studies following two specialist programmes, namely the cancer fast-track programme 29 and the LC strategist programme 31 . The latter study found that the time from suspicious imaging to definitive management plan was 14.5 days in the LC strategist programme and 46.5 days in routine referral ( p  < 0.001) 31 . It was also found that referral to the programme moved patients into low-risk nodule surveillance approximately one month earlier relative to routine referral (12.5 vs 39 days respectively, p  < 0.001). Compared to routine referral, management through the programme also significantly reduced the median number of hospital trips (4 vs 6 respectively, p  < 0.001), median number of clinicians seen (1.5 vs 2 respectively, p  = 0.08), median number of diagnostic studies obtained (4 vs 5 respectively, p  = 0.01), median time from suspicious radiological findings to diagnosis (30.5 vs 48 days respectively, p  = 0.02), and median time from suspicious radiological findings to treatment (40.5 vs 68.5 days respectively, p  = 0.02) 31 . Moreover, time from suspicious radiological findings to surgical resection was significantly shorter in patients managed through the programme in comparison to routine referral (38 vs 69 days respectively, p  = 0.05). Among patients with early-stage non-small cell LC treated with radiation therapy, the LC strategist programme led to a substantial reduction in the time from suspicious radiological findings to initiation of treatment in comparison to routine referral (62.5 vs 122.5 days respectively, p  = 0.08) 31 . Conversely, in the cancer fast-track programme, Prades et al. 29 noted a variable trend in mean time from detection of suspected LC in primary care to start of initial treatment. The 30-day target was not achieved, with mean times of 30.8 days, 38.9 days, 32.25 days, and 36.7 days in 2006, 2007, 2008, and 2009 respectively. There was also an increase in the proportion of patients waiting between 30 and 45 days (23.7% in 2006 vs 26.1% in 2009) and over 45 days (13.6% in 2006 vs 22.6% in 2009) from the time of LC detection to initiation of treatment.

Achieving early diagnosis is an essential step in improving LC outcomes 28 , 29 , 30 , 31 , 34 . While more than 85% of patients subsequently diagnosed with cancer initiate their diagnostic pathway in primary care 35 , timely recognition and referral of people with suspected LC is complicated by various primary HCP and system-related factors. For example, a scoping review of 33 studies identified low index of suspicion, delays in obtaining access to diagnostic tests, multiple specialist consultations and lack of rapid assessment services as barriers to early diagnosis of LC 36 . Additionally, a qualitative study of 16 GPs from five practices in the United Kingdom found that GPs often required high levels of suspicion to refer patients to secondary care and were concerned about overloading the healthcare system by over-referring patients 37 . More recently, Saab et al. 38 interviewed 36 primary HCPs (GPs, community pharmacists, GP practice nurses, and public health nurses) about their experience of referring individuals with suspected LC in Ireland. It was found that “typical” LC lung signs and symptoms such as cough and haemoptysis triggered referrals, whereas “atypical” signs and symptoms like back pain and pallor, were perceived as difficult to interpret. Participants suggested educating primary HCPs about early LC referral using “communications from professional organisations, webinars, interdisciplinary meetings, education by lung specialists, and patient testimonials” (p.1) 38 . The use of simple, clear, and visually appealing LC referral checklists and algorithms in primary care was also recommended 38 .

Several studies included in the present review reported on efforts to raise awareness of LC signs and symptoms among HCPs, and prompt timely referral for further diagnostic or specialist evaluation. These included: a combined public and HCP LC awareness campaign which used GP education resource cards with symptom risk assessment charts to increase symptom awareness and early specialist referral among GPs; 30 a push-pull campaign that involved educating GPs and community pharmacists about chest X-ray referral criteria for symptomatic patients; 32 and CME sessions for GPs addressing the indications for LDCT for signs and symptoms that raised GPs’ suspicion of LC, but fell short of satisfying the fast-track referral criteria 33 , 34 . Indeed, the effect of CME meetings on raising GPs’ awareness of cancer signs and symptoms and prompting early referral is well documented in the wider literature. Toftegaard et al. 39 studied the impact of CME meetings in Denmark to support GPs in recognising and referring patients with cancer warning signs and symptoms. An evaluation of this initiative found that CME meetings significantly improved knowledge of cancer among GPs and increased the number of urgent referrals 39 , which is associated with better cancer survival 40 , 41 .

Interventions that were successful in reducing the diagnostic interval included a multi-modal quality improvement project in primary care 28 and the LC strategist programme in secondary care 31 . In contrast, statistically significant reductions in diagnostic intervals were not achieved following a community- and GP-targeted awareness campaign 30 as well as information for GPs on LDCT for symptomatic patients 34 . GP participation in a 1-h CME session on LDCT, however, was associated with shorter primary care and diagnostic intervals 34 , higher absolute number of referrals to LC fast-track, and higher PPV for LC diagnosis 33 .

Postal questionnaires offer a pro-active, if somewhat resource intensive, option for primary HCPs to prompt help-seeking among high-risk symptomatic patients. For example, Wagland et al. 42 studied the impact of sending a postal symptom questionnaire, incorporating nine symptoms of LC, to patients identified as high risk for LC in eight GP practices in England. Through this intervention, a small, clinically relevant group (6.7%, n  = 61/908) of primary care patients was identified who, despite reporting potential symptoms of LC, had not consulted a GP in ≥12 months. Primary care consultations significantly increased in the 3-month period following receipt of the symptom elicitation questionnaire compared to the 3-month period pre-questionnaire ( p  = 0.002) 42 . Participants who decided not to consult their GP cited concerns over wasting their own and the GP time and reported a high symptom tolerance threshold and a greater tendency to self-manage their symptoms 42 . These barriers are well documented in the wider literature 15 , 16 , 18 .

The benefits of cancer fast-track pathways/programmes are well documented in the international literature 43 , 44 , 45 , 46 . Fast-track referral criteria are typically based on the presence of combinations of, or individual, ‘alarm’ cancer signs and symptoms and/or relevant radiological findings, usually with a PPV for cancer of 3% or above 47 . Two of the reviewed studies evaluated the impact of specialist-led and fast-track programmes on time from suspicious radiologic findings 31 and LC detection 29 to the planning and initiation of treatment. In comparison to routine referral, the specialist-led LC strategist programme significantly reduced the intervals between suspicious radiologic findings and definitive management plan, diagnosis, and treatment 31 . In contrast, in their evaluation of a cancer fast-track programme from its inception in 2006 until 2009, Prades et al. 29 reported a significant increase in waiting times from LC detection to initiation of treatment. This may be explained by factors including the complexity of LC treatment, including thoracic surgery at tertiary hospitals 29 .

Interventions aimed at prompting early referral and diagnostic work-up do not always lead to significant improvements in stage of LC at diagnosis and overall survival. Our systematic review demonstrated that CME sessions on the indications for LDCT 34 , the specialist-led LC strategist programme 31 , and a combined public and HCP cancer awareness campaign 32 , were not associated with significant differences in stage of LC at diagnosis. In addition, Philips et al. 31 found non-statistically significant differences in LC recurrence and mortality in patients referred through the LC strategist programme in comparison to those referred through routine referral. Larger scale studies with more statistical power and prospective RCTs with longer follow-up are recommended 31 , 32 , 34 .

This review offers valuable insights into interventions aimed at improving the early diagnosis of symptomatic LC. However, a few limitations are worthy of note. While there is some evidence for the effectiveness of CME meetings and fast-track programmes, recommendations for clinical practice should be made with caution, particularly due to the small number of studies included in this review and the fact that meta-analyses were not possible due to significant heterogeneity in study design, interventions, and outcome measures. Study selection bias could have occurred, as only studies relevant to the review aims were included, the search did not include records from the grey literature or clinical trial registries, and the review was limited to studies published within a 10-year timeframe.

In conclusion, findings from this review indicate that CME meetings for primary HCPs may facilitate early LC referral, diagnosis, and survival. We also found evidence that fast-track programmes, such as the LC strategist programme 31 , may improve time from initial presentation with symptoms in primary care to LC diagnosis, and time from diagnosis to treatment, in addition to reducing hospital visits and the number of clinicians seen between initial presentation and initiation of treatment. However other interventions, such as awareness campaigns, were not associated with significant improvements in outcomes 30 , 32 . Outcomes such as LC stage shift and mortality rates were seldom measured in the reviewed studies. When measured, statistical significance was not reached, hence the importance of conducting future studies that are appropriately powered, controlled, and have longer follow-up.

Review findings may inform cancer control policy, including the design and implementation of interventions aimed at overcoming barriers to early LC diagnosis. These interventions may include awareness and education campaigns targeting the public and HCPs, and implementation of specialist-led fast-track referral programmes to facilitate timely diagnosis.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68 , 394–424 (2018).

Article   PubMed   Google Scholar  

World Health Organization International Agency for Research on Cancer. Cancer Tomorrow . https://gco.iarc.fr/tomorrow/en/dataviz/isotype?cancers=15&single_unit=100000&types=0 (2020).

Torre, L. A., Siegel, R. L., & Jemal, A. Lung cancer statistics. Lung Cancer and Personalized Medicine , 1–19 (Springer, Cham, 2016).

Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J. Clinicians 71 , 209–249 (2021).

Google Scholar  

Koo, M. M., Hamilton, W., Walter, F. M., Rubin, G. P. & Lyratzopoulos, G. Symptom signatures and diagnostic timeliness in cancer patients: a review of current evidence. Neoplasia 20 , 165–174 (2018).

Saab, M. M., Landers, M. & Hegarty, J. Exploring awareness and help-seeking intentions for testicular symptoms among heterosexual, gay, and bisexual men in Ireland: a qualitative descriptive study. Int. J. Nurs. Stud. 67 , 41–50 (2017).

O’Mahony, M., McCarthy, G., Corcoran, P. & Hegarty, J. Shedding light on women’s help seeking behaviour for self discovered breast symptoms. Eur. J. Oncol. Nurs. 17 , 632–639 (2013).

Okoli, G. N., Kostopoulou, O. & Delaney, B. C. Is symptom-based diagnosis of lung cancer possible? A systematic review and meta-analysis of symptomatic lung cancer prior to diagnosis for comparison with real-time data from routine general practice. PLoS ONE 13 , e0207686 (2018).

Article   PubMed   PubMed Central   Google Scholar  

Chowienczyk, S., Price, S. & Hamilton, W. Changes in the presenting symptoms of lung cancer from 2000–2017: a serial cross-sectional study of observational records in UK primary care. Br. J. Gen. Pract. 70 , e193–e199 (2020).

American Cancer Society. Signs and Symptoms of Lung Cancer . https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/signs-symptoms.html (2019).

Walter, F. M. et al. Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study. Br. J. Cancer 112 , S6–S13 (2015).

Holmberg, L. et al. National comparisons of lung cancer survival in England, Norway and Sweden 2001–2004: differences occur early in follow-up. Thorax 65 , 436–441 (2010).

Ellis, P. M. & Vandermeer, R. Delays in the diagnosis of lung cancer. J. Thorac. Dis. 3 , 183 (2011).

PubMed   PubMed Central   Google Scholar  

Saab, M. M. et al. Promoting lung cancer awareness, help-seeking and early detection: a systematic review of interventions. Health Promotion Int. 36 , 1656–1671 (2021).

Article   Google Scholar  

Saab, M. M. et al. Awareness and help-seeking for early signs and symptoms of lung cancer: a qualitative study with high-risk individuals. Eur. J. Oncol. Nurs. 50 , 101880 (2021).

Cassim, S. et al. Patient and carer perceived barrriers to early presentation and diagnosis of lung cancer: a systematic review. BMC Cancer 19 , 25 (2019).

Cunningham, Y. et al. Lung cancer symptom appraisal among people with chronic obstructive pulmonary disease: a qualitative interview study. Psychooncology 28 , 718–725 (2019).

Saab, M. M. et al. Primary healthcare professionals’ perspectives on patient help-seeking for lung cancer warning signs and symptoms: a qualitative study. BMC Prim. Care 23 , 119 (2022).

Bradley, S. H., Kennedy, M. & Neal, R. D. Recognising lung cancer in primary care. Adv. Ther. 36 , 19–30 (2019).

Higgins, J. P. T. et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane . www.training.cochrane.org/handbook (2022).

Page, M. J. et al. Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement. J. Clin. Epidemiol. 134 , 103–112 (2021).

Schardt, C., Adams, M. B., Owens, T., Keitz, S. & Fontelo, P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med. Inform. Decis. Mak. 7 , 1–6 (2007).

The Cochrane Collaboration. Covidence . https://community.cochrane.org/help/tools-and-software/covidence (2022).

Saab, M. M. et al. Referring high-risk individuals for lung cancer screening: a systematic review of interventions with healthcare professionals. Eur. J. Cancer Prev . 31 , 540–550 (2022).

Popay, J. et al. Guidance on the conduct of narrative synthesis in systematic reviews. A product from the ESRC Methods Programme . Version 1, b92. https://www.lancaster.ac.uk/media/lancaster-university/contentassets/documents/fhm/dhr/chir/NSsynthesisguidanceVersion1-April2006.pdf (2006).

Hong, Q. N. et al. The Mixed Methods Appraisal Tool (MMAT) version 2018 for information professionals and researchers. Educ. Inf. 34 , 285–291 (2018).

Scottish Intercollegiate Guidelines Network. Healthcare Improvement Scotland: A Guideline Developer’s Handbook . https://www.sign.ac.uk/assets/sign50_2011.pdf (2011).

Apthorp, C. et al. Assessment of serum calcium in patients referred for suspected lung cancer: a quality improvement project to enhance patient safety in clinical practice. Future Healthc. J. 8 , e109 (2021).

Prades, J., Espinas, J. A., Font, R., Argimon, J. M. & Borras, J. M. Implementing a Cancer Fast-track Programme between primary and specialised care in Catalonia (Spain): a mixed methods study. Br. J. Cancer 105 , 753–759 (2011).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Emery, J. D. et al. The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia. Br. J. Cancer 117 , 1459–1469 (2017).

Phillips, W. W. et al. Lung Cancer Strategist Program: a novel care delivery model to improve timeliness of diagnosis and treatment in high-risk patients. Healthcare 9 , 100563 (2021).

Athey, V. L., Suckling, R. J., Tod, A. M., Walters, S. J. & Rogers, T. K. Early diagnosis of lung cancer: evaluation of a community-based social marketing intervention. Thorax 67 , 412–417 (2012).

Guldbrandt, L. M., Rasmussen, T. R., Rasmussen, F. & Vedsted, P. Implementing direct access to low-dose computed tomography in general practice—method, adaption and outcome. PLoS ONE 9 , e112162 (2014).

Guldbrandt, L. M. et al. The effect of direct access to CT scan in early lung cancer detection: an unblinded, cluster-randomised trial. BMC Cancer 15 , 1–11 (2015).

Hansen, R. P., Vedsted, P., Sokolowski, I., Søndergaard, J. & Olesen, F. Time intervals from first symptom to treatment of cancer: a cohort study of 2,212 newly diagnosed cancer patients. BMC Health Serv. Res. 11 , 1–8 (2011).

Malalasekera, A. et al. How long is too long? A scoping review of health system delays in lung cancer. Eur. Respir. Rev. 27 , 180045 (2018).

Wagland, R. et al. Facilitating early diagnosis of lung cancer amongst primary care patients: the views of GPs. Eur. J. Cancer Care 26 , e12704 (2017).

Saab, M. M. et al. Referring patients with suspected lung cancer: a qualitative study with primary healthcare professionals in Ireland. Health Promotion Int. 37 , 1–12 (2022).

Toftegaard, B. S., Bro, F., Falborg, A. Z. & Vedsted, P. Impact of continuing medical education in cancer diagnosis on GP knowledge, attitude and readiness to investigate–a before-after study. BMC Fam. Pract. 17 , 1–10 (2016).

Toftegaard, B. S., Bro, F., Falborg, A. Z. & Vedsted, P. Impact of a continuing medical education meeting on the use and timing of urgent cancer referrals among general practitioners-a before-after study. BMC Fam. Pract. 18 , 1–13 (2017).

Møller, H. et al. Use of the English urgent referral pathway for suspected cancer and mortality in patients with cancer: cohort study. BMJ 351 , h5102 (2015).

Wagland, R. et al. Promoting help-seeking in response to symptoms amongst primary care patients at high risk of lung cancer: a mixed method study. PLoS ONE 11 , e0165677 (2016).

Stapley, S. et al. The risk of pancreatic cancer in symptomatic patients in primary care: a large case–control study using electronic records. Br. J. Cancer 106 , 1940–1944 (2012).

Howell, D. A. et al. Time-to-diagnosis and symptoms of myeloma, lymphomas and leukaemias: a report from the Haematological Malignancy Research Network. BMC Blood Disord. 13 , 1–9 (2013).

Din, N. U. et al. Age and gender variations in cancer diagnostic intervals in 15 cancers: analysis of data from the UK Clinical Practice Research Datalink. PLoS ONE 10 , e0127717 (2015).

Zhou, Y. et al. Variation in ‘fast-track’ referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites. Br. J. Cancer 118 , 24–31 (2018).

Article   CAS   PubMed   Google Scholar  

National Collaborating Centre for Cancer. Suspected Cancer: Recognition And Referral . https://www.nice.org.uk/guidance/ng12/evidence/full-guideline-pdf-2676000277 (2015).

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The authors would like to thank the National Cancer Control Programme, Health Services Executive, Ireland for funding this research.

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M.M.S., H.E.B., U.K., Á.L. and J.H. contributed to study conception. M.M.S., M.Mc.C., M.O’.D., L.J.S., P.L.-W., B.N., S.F., M.O’.M. and N.L. performed screening, data extraction, and quality appraisal. M.M.S. and M.Mc.C. drafted the manuscript and all authors provided critical revisions and editing of the manuscript.

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Saab, M.M., McCarthy, M., O’Driscoll, M. et al. A systematic review of interventions to recognise, refer and diagnose patients with lung cancer symptoms. npj Prim. Care Respir. Med. 32 , 42 (2022). https://doi.org/10.1038/s41533-022-00312-9

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Clinical presentation and in-hospital prognosis of lung cancer patients presenting with suspected and confirmed COVID-19

Affiliations.

• 1 Departamento de Oncologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
• 2 Centro de Pesquisa Clínica e Epidemiológica, Hospital Universitário, Universidade de São Paulo, São Paulo, SP, Brasil.
• PMID: 36102415
• PMCID: PMC9467285
• DOI: 10.1590/1414-431X2022e12140

We sought to compare the clinical presentation and prognosis of patients with lung cancer and confirmed COVID-19 infection to those with negative RT-PCR SARS-CoV-2 results. We included patients with confirmed lung cancer and suspected COVID-19 who presented to the emergency department. The primary outcome was in-hospital mortality and secondary outcomes included admission to intensive care unit (ICU) or mechanical ventilation. We analyzed the characteristics according to RT-PCR results and primary outcome. We constructed a logistic regression for each RT-PCR result group to find potential predictors of the primary outcome. Among 110 individuals with confirmed lung cancer (65±9 years, 51% male), 38 patients had positive RT-PCR and 72 patients had negative RT-PCR. There was no difference between groups for any clinical characteristic or comorbidities though individuals with confirmed COVID-19 had higher functionality in the ECOG scale. Leucocytes and lymphocytes were lower in individuals with positive tests. The primary outcome occurred in 58 (53%) individuals, 37 (34%) were admitted to the ICU, and 29 (26%) required mechanical ventilation. Although mortality was similar between the two groups, individuals with confirmed COVID-19 were significantly more likely to be admitted to the ICU or receive mechanical ventilation. Only lower lymphocytes and higher CRP were significantly associated with higher mortality. The clinical presentation of COVID-19 in lung cancer is not sufficient to identify higher or lower probability groups among symptomatic individuals, the overall mortality is high irrespective of RT-PCR results, and lymphopenia on admission was associated with the diagnosis and prognosis for COVID-19.

• COVID-19* / diagnosis
• Hospital Mortality
• Lung Neoplasms* / diagnosis

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• CARDIAC SURGERY
• RESPIRATORY
• VASCULAR SURGERY

Clinical Presentation of Lung Cancer

Clinical Presentation of Lung Cancer Matthew G. Blum As one of the most common malignancies in the world, lung cancer presents with widely varied signs, symptoms, and syndromes. Some 93% of lung cancer patients present with symptoms. Unfortunately early-stage lung cancer is rarely symptomatic. Even when symptoms of early cancer are present, they are generally not specific and frequently mimic more common disease. Consequently most patients present in advanced stages with metastases and ultimately die of their disease. A recent study of the presentation of lung cancer in 1,154 patients found that 98% of symptomatic patients had stage III or IV disease (versus 46% of asymptomatic patients). 52 Reports examining the prevalence of particular presenting symptoms vary widely owing to differing study designs, patient populations, and the time period studied. The most common symptoms from several recent series are cough and dyspnea ( Table 107-1 ). However, the spectrum of lung cancer presentation remains extremely broad because it includes symptoms caused by local invasion, metastases, and paraneoplastic mechanisms. Paraneoplastic syndromes occur in only 2% of patients with lung cancer but cause the widest variety of symptoms and syndromes ( Table 107-2 ). Much of the information about lung cancer presentation refers to data from the 1960s through 1980s, before computed tomography (CT) scanning. Since then there has been a shift in demographics to more elderly patients, women, and adenocarcinoma histology, which may be changing the relative proportions of presenting signs or symptoms. In a report detailing the presentation of 1,277 lung cancer patients between 1989 and 2002, fewer patients presented with cough or chest pain and more were asymptomatic in more recent periods. 5 The increasing use of helical CT and high-resolution CT scanning as a lung cancer screening tool and in the evaluation of other medical conditions may account for the increase in asymptomatic lesions detected. Whether by clinical symptoms or radiographic imaging, diagnosing lung cancer relies on having a high index of suspicion in the appropriate setting. Tobacco smoking is clearly recognized as the major cause of lung cancer, but a myriad of other exposures and patient characteristics have been related to the development of lung cancer. Environmental exposures to secondhand smoke, 20 silica, creosotes, and mining of gold, nickel, asbestos, and uranium have all been associated with increased risk of lung cancer. Individuals with autoimmune diseases such as scleroderma and idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and particular treatments such as chemotherapy for Hodgkin’s lymphoma are also at higher risk of developing lung cancer. 51 A familial predilection to lung cancer, even in nonsmokers, suggests that genetics may also predispose some patients to lung cancer. The incidence of lung cancer increases with age. As a result, young patients (<40 years of age), women, and nonsmokers are more likely to have their symptoms attributed to benign causes. This lower index of suspicion probably accounts for those <40 presenting with higher-stage disease. 4 , 55 Lung cancers appearing <40 years of age are more common in women. 23 Adenocarcinoma is also more frequently found in those <40 years of age. 4 , 23 , 55 The increased use of cigarettes by women has resulted in a parallel increase in the prevalence of lung cancer in women. Local Symptoms Bronchopulmonary Symptoms Cough Cough is the most common presenting symptom of lung cancer ( Table 107-1 ), but it is frequently overlooked because it is far more often associated with infections or chronic bronchitis. Cancer-associated cough is caused by airway irritation secondary to mass effect, inflammatory response to cancer, mucin production, or obstruction-causing pneumonia. Smokers frequently have a chronic cough, but changes in the character (sputum production, frequency) of the cough should prompt further evaluation. There are no particular characteristics that distinguish benign from malignant causes of cough. However, cough with associated symptoms (weight loss, anorexia, or hemoptysis) or laboratory abnormalities (spirometric or thrombocytosis) increases the likelihood of a cancer diagnosis. 12 Hemoptysis Hemoptysis is generally an alarming symptom that leads to rapid presentation to the medical system. Inflammatory diseases still account for most cases of hemoptysis, although the rising incidence of lung cancer makes it increasingly common as a cause of hemoptysis. Some 13% to 40% of patients presenting with hemoptysis have lung cancer. 15 , 54 Hemoptysis may also be the earliest symptom of occult cancer, and a thorough evaluation should be undertaken to establish a cause. In a multivariate analysis of symptoms present 180 days or more prior to the diagnosis of lung cancer, hemoptysis was the symptom most likely to be associated with cancer. 8 Of 722 patients presenting to a pulmonologist for evaluation of hemoptysis who had no bleeding source found during the initial evaluation, 6% ultimately were diagnosed with lung cancer. 9 Bronchoscopy and chest radiography should be used routinely to evaluate hemoptysis. A CT scan of the chest should follow a negative bronchoscopic examination and chest radiograph. If initial studies fail to determine a cause of hemoptysis, interval CT scans should be obtained. Table 107-1 Common Symptoms of Lung Cancer Presentation Symptom Percent Cough 24–68 Dyspnea 17–59 Hemoptysis 5–41 Hoarseness 2–15 Chest pain 5–64 Extrathoracic pain 8–36 Neurologic 10–12 Weight loss 27–50 Anorexia 19–64 Fatigue 8–68 Sources: Data drawn from references 5 , 7 , 12 , 22 , and 52 . Hemoptysis from lung cancer is generally small to moderate in volume (<500 mL/24 hours). 17 , 39 Possible sources of hemoptysis include systemic supply from the bronchial arteries or collaterals and pulmonary supply from the pulmonary artery or veins. Severe systemic arterial bleeding may be controlled by embolization. Carcinoma-induced hemoptysis frequently has a multisource blood supply, and this, as compared with other causes of hemoptysis, has reduced the success of embolization. 10 , 14 , 39 , 49 Survival after embolization for lung cancer–induced hemoptysis is less than 4 months. 14 Erosion of tumor into pulmonary arteries or systemic vessels is often massive and fatal. Tumor erosion into the heart itself has been reported as a cause of fatal hemoptysis. 30 Despite these reports, lung cancer is rarely a cause of massive hemoptysis. Wheezing or Stridor Lung cancer can cause airway obstruction and turbulent airflow, resulting in the harshness of stridor or musical wheezing. Both intrinsic obstruction by tumor mass and extrinsic airway compression by tumor or adenopathy may cause obstruction. Stridor generally indicates tracheal obstruction and occurs when >50% of the lumen is obstructed. Occasionally central mainstem bronchial tumors may create stridor. Wheezing caused by lung cancer (in contrast to polyphonic diffuse asthmatic wheezing) is often monophonic and localized around the area of obstruction. Both stridor and wheezing from tumors involving the trachea are occasionally diagnosed as adult-onset asthma. Stridor is an inspiratory noise and should not be mistaken for the expiratory wheezing of asthma. Neither stridor nor wheezing caused by cancer responds well to bronchodilators. Chest radiographs are often unrevealing, but CT scanning will usually show intraluminal mass or extrinsic compression by tumor or adenopathy. Bronchoscopy is usually diagnostic when symptomatic airway involvement is present. Table 107-2 Paraneoplastic Syndromes in Lung Cancer Patients Metabolic   Hypercalcemia   Cushing’s syndrome   Inappropriate production of antidiuretic hormone   Carcinoid syndrome   Gynecomastia   Hypercalcitoninemia   Elevated growth hormone level   Elevated levels of prolactin, follicle-stimulating hormone, and luteinizing hormone   Hypoglycemia   Hyperthyroidism Neuromuscular   Encephalopathy   Polymyositis   Autonomic neuropathy   Lambert—Eaton syndrome   Opsoclonus and myoclonus   Gastrointestinal neuropathy   Polymyositis/dermatomyositis   Limbic encephalitis   Cortical cerebellar degeneration   Spinal cerebellar degeneration   Dementia   Subacute necrotic myelopathy   Peripheral neuropathies (cranial nerves, sensorimotor, sensory)   Cancer-associated retinopathy   Internuclear ophthalmoplegia Skeletal   Clubbing   Pulmonary hypertrophic osteoarthropathy Hematologic   Anemia   Leukemoid reactions   Thrombocytosis   Thrombocytopenia   Eosinophilia   Pure red cell aplasia   Leukoerythroblastosis   Disseminated intravascular coagulation   Hypercoagulability   Hypocoagulability Cutaneous and muscular   Hyperkeratosis   Dermatomyositis   Acanthosis nigricans   Hyperpigmentation   Erythema gyratum repens   Hypertrichosis lanuginosa acquisita Other   Nephrotic syndrome   Hypouricemia   Secretion of vasoactive intestinal peptide with diarrhea   Hyperamylasemia   Anorexia—cachexia Dyspnea Lung cancer may cause dyspnea by multiple different mechanisms. Airway obstruction can cause atelectasis distal to the obstruction. The amount of lung parenchyma involved may vary from only a subsegmental area of lung parenchyma to an entire lung, depending on the site and degree of airway obstruction. Similarly, obstruction or compression of the pulmonary artery or branches may result in areas of defunctionalized lung secondary to hypoperfusion. Ventilation/perfusion mismatch in either case may cause dyspnea. Postobstructive pneumonia can similarly result in dyspnea. Additionally, tumor infiltration of lung parenchyma or increased lung water from inhibition of lymphatic drainage can result in increased alveolar thickness, less efficient gas diffusion, and relative shunting. Pleural effusions frequently cause dyspnea. Symptomatic effusions from lung cancer most commonly contain malignant cells. Less common causes of dyspnea are phrenic nerve paralysis and pericardial effusion. Postobstructive Infectious Symptoms Tumors that obstruct airways inhibit airway drainage, allowing colonization and overgrowth of bacteria. The resulting postobstructive pneumonia can cause fever and leukocytosis, malaise, and weight loss. Chest imaging may be unable to reliably distinguish tumor mass from a pneumonic process. Therefore patients treated with antibiotics should have a follow-up radiography to confirm complete resolution of infiltrates. Recurrent pneumonia in the same location should prompt CT scanning and bronchoscopy to exclude intraluminal tumor or an anatomic basis for recurrence. Nonbronchopulmonary Symptoms Pain Chest wall pain may bring patients to medical attention. Pleural-based pain may be due to direct irritation of the parietal pleura by either inflammation from postobstructive pneumonia or direct invasion by tumor. Tumor invasion or metastasis to ribs may create bone pain. Additionally, sensory nerve invasion (intercostal or brachial plexus) can lead to neuropathic pain. Chest wall pain in the region of known tumor should raise the suspicion of chest wall invasion. Preoperative evaluation should include imaging of the region to define depth of invasion and involved structures. When complex neurovascular structures are involved (such as the apex of the chest or spine), magnetic resonance imaging (MRI) provides better anatomic definition than CT scanning. Operations on patients who have chest wall pain should include a strategy for en bloc chest wall resection. Diffuse facial pain from lung cancer may be caused by invasion of the ipsilateral vagus nerve and relieved by treatment of the primary tumor. 1 Pancoast Syndrome Superior sulcus tumors may invade the brachial plexus and stellate ganglion, presenting with a constellation of signs and symptoms known as Pancoast’s syndrome. These include ipsilateral Horner’s syndrome (facial anhydrosis, miosis, and ptosis) as well as neuritic pain and muscular atrophy in the arm and hand. Horner’s syndrome is caused by direct tumor invasion of the stellate ganglion. Tumor invasion of the lower brachial plexus cords (C7, C8, T1) leads to inner arm pain and wasting of intrinsic muscles of the hand. Vertebral body or rib destruction results in bone pain. Direct invasion of intercostal nerves can also cause chest wall and inner arm (via intercostobrachial branch) pain. Although locally invasive, Pancoast tumors are frequently amenable to treatment with multimodality therapy, including surgical resection. Dysphagia Dysphagia occurs rarely as a presenting complaint of lung cancer. When it does occur, it is usually due to esophageal compression, invasion from subcarinal nodal disease, or tension hydrothorax. Rarely, direct extension of tumor or involvement of paraesophageal nodes causes obstruction. Other Local, Potentially Symptomatic Consequences of Lung Cancer Growth Pleural Effusion Patients with dyspnea from lung cancer frequently have a malignant pleural effusion. The typically one-sided effusions result from an imbalance of pleural fluid production and resorption. Cancer patients may develop effusions from any of the following: Increased capillary permeability or hemorrhage from tumor implants Decreased oncotic pressure from hypoproteinemia Decreased absorption secondary to lymphatic obstruction by tumor Pleural effusions associated with lung cancer can be reactive, especially in the setting of postobstructive atelectasis or pneumonia. Thoracentesis and fluid cytology is indicated to establish the presence or absence of malignant cells prior to resection and in any cases where such staging would change the therapeutic plan. Occasionally, an effusion will be discovered incidentally as a radiographic abnormality and prompt additional evaluation that ultimately leads to the diagnosis of lung cancer. In a report of 860 pleural effusion specimens from patients without known lung cancer, cytology demonstrated lung cancer in 2%. 31 All died within 19 months of diagnosis, attesting to the poor survival of patients presenting with malignant effusions. Mesothelioma frequently presents with malignant pleural effusion. Directed pleural biopsy, usually thoracoscopic, is encouraged to evaluate recurrent pleural effusions with nondiagnostic cytology.

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Clinical Presentation of Lung Cancer

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Beckles AM, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer. Symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest 2003; 123:97S.

Article   PubMed   Google Scholar  

Scagliotti GV. Symptoms, signs and staging of lung cancer. Eur Respir Mon 2001; 17:86.

Google Scholar  

Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004; 350:379.

Article   PubMed   CAS   Google Scholar  

Fraser RS, Müller NL, Colman N, Paré PD. Fraser and Paré’s Diagnosis of Diseases of the Lung. WB Saunders, Philadelphia, 1999.

Gerber RB, Mazzone P, Arroliga AC. Paraneoplastic syndromes associated with bronchogenic carcinoma. Clin Chest Med 2002; 23(1):257.

Grippi MA. Clinical aspects of lung cancer. Semin Roentgenol 1990; 25:12.

Santiago SM, Lehrman S, Williams AJ. Bronchoscopy in patients with haemoptysis and normal chest roentgenograms. Br J Dis Chest 1987; 81(2):186.

Snider GL, Placik B. The relationship between pulmonary tuberculosis and bronchogenic carcinoma: a topographic study. Am Rev Respir Dis 1969; 99(2):229.

PubMed   CAS   Google Scholar  

Mountain CF, Dresler CM. Regional lymph node classifycation for lung cancer staging. Chest 1997; 111:1718.

Pancoast HK. Superior pulmonary sulcus tumor: tumor characterized by pain, Horner’s syndrome, destruction of bone and atrophy of hand muscles. JAMA 1932; 99:1391.

Arcasoy SM, Jett JR. Superior pulmonary sulcus tumors and Pancoast syndrome. N Engl J Med 1997; 337:1370.

Paulson DL. Treatment of superior sulcus carcinoma. In: Fishmans AP (ed.) Update: Pulmonary Diseases and Disorders. McGrow and Hill, New York, 1982; p 318.

Jett JR. Superior sulcus tumors and Pancoast’s syndrome. Lung Cancer 2003; 42:S17.

Komaki R, Roth JA, Walsh GL, Putnam JB, Vaporciyan A, Lee JS, Fossella FV, Chasen M, Delclos ME, Cox JD. Outcome predictors for 143 patients with superior sulcus tumors treated by multidisciplinary approach at the University of Texas MD Anderson Cancer Center. Int J Radiat Oncol Biol Phys 2000; 48:347.

Archie VC, Thomas CR. Superior sulcus tumors: a mini review. Oncologist 2004; 9:550.

Yellin A, Rosen A, Reichert N, Lieberman Y. Superior vena cava syndrome: the myth — the facts. Am Rev Respir Dis 1990; 141:1114.

Wudel LJ, Nesbitt JC. Superior vena cava syndrome. Curr Treat Options Oncol 2001; 2(1):77.

PubMed   Google Scholar  

Rowel NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 2002; 14:338.

Light RW Pleural Diseases, 4th edn. Lippincott, Williams and Wilkins, Philadelphia, 2001.

Rodriguez-Panadero F. Lung cancer and ipsilateral pleural effusion. Ann Oncol 1995; 6:S25.

Wilkes JD, Fidias, P, Vaickus, L, Perez, RP. Malignancy-related pericardial effusion. 127 cases from the Roswell Park Cancer Institute. Cancer 1995; 76:1377.

Laham RJ, Cohen DJ, Kuntz RE, Baim DS, Lorell BH, Simons M. Pericardial effusion in patients with cancer: outcome with contemporary management strategies. Heart 1996; 75:67.

Allen KB, Faber LP, Warren WH, Shaar CJ. Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter drainage. Ann Thorac Surg 1999; 67:437.

Tsang TSM, Freeman WK, Sinak LJ, Seward JB. Echocardiographically guided pericardicentesis: evolution and state-of-the-art technique. Mayo Clin Proc 1998; 73(7):647.

Pauzner R, Istomin V, Segal-Lieberman G Matetzky S, Farfel Z. Bilateral patellar metastases as the clinical presenta tion of bronchogenic adenocarcinoma. J Rheum 1996;23:939.

Andersen HA, Prakash UBS. Diagnosis of symptomatic lung cancer. Semin Respir Med 1982; 3:165.

Mendelsohn G, Baylin SB. Ectopic hormone production: biological and clinical implications. Prog Clin Biol Res 1984; 142:291.

Dimopoulos AM, Fernandez JF, Samaan NA Holoye PY, Vassilopoulou-Sellin R. Paraneoplastic Cushing’s syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer. Cancer 1992; 69:66.

Johnson BE, Chute JP, Rusdin J, Williams J, Le PT, Venzon D, Richardson GE. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997; 156(5):1669.

Williams ED, Azzopardi JG. Tumours of the lung and the carcinoid syndrome. Thorax 1960; 15:30.

Posner JB, Dalmau J. Paraneoplastic syndromes. Curr Opin Immunol 1997; 9:723.

Kurzrock R, Cohen PR. Cutaneous paraneoplastic syndromes in solid tumors. Am J Med 1995; 99(6):662.

Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 66; 14.

Masin N, Buchard PA, Gerster JC. Polymyalgia rheumatica et cancer pulmonaire: syndrome paraneoplastique. Rev Rheum Mai Osteoartic 1992; 59:153.

CAS   Google Scholar  

Naschitz JE, Rosner I, Rozenbaum M, Zuckerman E, Yeshurun D. Rheumatic syndromes: clues to occult neoplasia. Semin Arthritis Rheum 1999; 29(1):43.

Fam AG. Paraneoplastic rheumatic syndromes. Baillieres Best Pract Res Clin Rheumatol 2000; 14(3):515.

Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987; 2:1434.

Dickinson CJ. The aetiology of clubbing and hypertrophic osteoarthropathy. Eur J Clin Invest 1993; 23(6):330.

Meyers KA, Farquhar DR. The rational clinical examination. Does this patient have clubbing? JAMA 2001; 286(3):341.

Article   Google Scholar  

Martinez-Lavin M. Hypertrophic osteoarthropathy. Curr Opin Rheumatol 1997; 9(1):83.

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Charis Roussos MD, MSc, PhD, MRS, FRCP(C)

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Papiris, S.A., Roussos, C. (2006). Clinical Presentation of Lung Cancer. In: Syrigos, K.N., Nutting, C.M., Roussos, C. (eds) Tumors of the Chest. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-31040-1_9

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• Published: 06 April 2024

Real-world patient characteristics and treatment patterns in US patients with advanced non-small cell lung cancer

• Hozefa A. Divan 1 ,
• Marisa A. Bittoni 2 ,
• Ashok Krishna 1 &
• David P. Carbone 2  

BMC Cancer volume  24 , Article number:  424 ( 2024 ) Cite this article

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Patients from non-small cell lung cancer (NSCLC) controlled clinical trials do not always reflect real-world heterogeneous patient populations. We designed a study to describe the real-world patient characteristics and treatment patterns of first-line treatment in patients in the US with NSCLC.

This was an observational, retrospective cohort study based on electronic medical records of US adults with locally advanced or metastatic disease in the ConcertAI Patient360 NSCLC database who initiated first-line treatment with anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy between July 2016 and December 2020. The analysis used patient attributes, clinical characteristics, and treatments from each patient’s medical records.

A total of 2175 patients were eligible for analysis. The median age was 68 years, and 26.2% of the patients were ≥75 years old. At treatment initiation, 96.4% and 3.6% of the patients had Stage 4 and Stage 3 (B or C) NSCLC, respectively. The most common histology type was nonsquamous adenocarcinoma (66.4%), and 19.8% had Eastern Cooperative Oncology Group performance status ≥2. Immunosuppressive medications were being used by 17.7% of patients, and 11.0% were immunocompromised. Almost all patients had metastases: 64.6% had 1, 23.2% had 2, and 8.0% had ≥3 metastatic sites. Brain metastases were present in 22.9% of patients. Treatment evolution was observed with first-line standard of care shifting from single-agent immunotherapy in 2016 (90.2%) to combination immunotherapy and chemotherapy in 2020 (60.2%).

Between 2016 and 2020, the first-line treatment paradigm for advanced NSCLC in the US shifted from anti–PD-1/PD-L1 monotherapy to combination chemoimmunotherapy, with increasing biomarker testing. Further research in heterogeneous patient populations to characterize treatment strategies is warranted.

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Lung cancer was the leading cause of cancer-related deaths worldwide in 2020, and approximately 70% of cases were locally advanced or metastatic disease at diagnosis, of which 80–85% were non-small cell lung cancer (NSCLC) [ 1 , 2 , 3 ].

Clinical trials in recent years have examined a variety of treatment strategies, including monotherapy and combination immunotherapy (IO) compared with chemo-therapy, the previous standard of care for advanced NSCLC [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. As a result, the treatment landscape for advanced NSCLC without actionable driver mutations in EGFR or ALK has shifted from chemotherapy to IO with chemotherapy. Immunotherapies target negative immunologic regulators such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway [ 16 ].

Between 2015 and 2021, IO agents approved by the United States (US) Food and Drug Administration (FDA) as first- or second-line therapy for NSCLC without driver mutations included: the anti–PD-1 antibodies nivolumab, pembrolizumab, and cemiplimab; the anti–PD-L1 antibodies durvalumab and atezolizumab; and the anti–CTLA-4 antibody ipilimumab [ 17 ]. Use of first-line IO to treat advanced NSCLC has increased substantially in the US since the initial approvals in 2016 [ 18 ]. First-line FDA approvals occurred for IO monotherapy with pembrolizumab in October 2016 and for pembrolizumab combination therapy with chemotherapy in May 2017 [ 19 ]. Atezolizumab combination therapy was approved in December 2018 [ 19 ]. Nivolumab + ipilimumab was approved in May 2020, along with atezolizumab monotherapy [ 19 ]. Finally, cemiplimab monotherapy was approved in February 2021 [ 19 ].

Clinical trials are designed to enroll selected patients (ie, those with good performance status, adequate organ function, without certain comorbidities, and who are not immunocompromised), and treatments are administered in highly controlled settings. Therefore, it can be challenging to generalize the findings to the more clinically heterogeneous patient populations seen in practice [ 18 ]. Here we report the findings from a real-world observational study that examined the ConcertAI Patient360 NSCLC database to describe key evidence gaps related to clinical characteristics and treatment patterns in patients in the US who initiated first-line treatment with IO mono-therapy or combination therapy for advanced NSCLC from 2016 to 2020.

Study design and data source

This was a non-interventional, observational, retrospective cohort study of patients with advanced NSCLC who received treatment as documented in the Patient360 NSCLC electronic medical record (EMR) database (ConcertAI, Cambridge, MA). This database sources patient EMRs, including unstructured notes and scans, from multiple oncologic partnerships that are EMR-system agnostic. The database consists of de-identified data from patients treated at various academic (~20%) and community (~80%) oncology centers across the US (~15% in the Northeast, ~25% in the Midwest, ~40% in the South, and ~20% in the West, as defined by US Census Bureau geographic regions).

The overall study period was from July 1, 2015, to March 31, 2021 (Fig. 1 ). The study design included a baseline period, a patient identification period, and a follow-up period. The index date was defined as the date on which the patient initiated first-line anti–PD-1/PD-L1 therapy for locally advanced or metastatic NSCLC. The baseline period spanned from the patient’s earliest NSCLC diagnosis in the database, starting from July 1, 2015, to the index date. If more than one assessment for the same variable of interest was available within this baseline period, the assessment closest to the index date was selected. During the patient identification period (July 1, 2016, to December 31, 2020; 3 months prior to the end of the follow-up period), eligible patients with advanced NSCLC who initiated first-line systemic treatment were identified. The follow-up period began one day post-index date and ended either on the date of death or on March 31, 2021 (end date of the database).

Study period timeline, including baseline period, patient identification period, index date, and follow-up period

The focus of this analysis was patients with advanced NSCLC who were treated with first-line anti–PD-1/PD-L1 therapy. Patients included in the final study cohort for this analysis (Fig. 2 ) had to have (i) a diagnosis of locally advanced, unresectable Stage 3B and 3C, or Stage 4 metastatic NSCLC; (ii) no evidence of candidacy for surgical reconstruction or definitive chemoradiation; (iii) started first-line therapy from July 1, 2016, through December 3, 2020; (iv) age ≥18 years at the time of first-line therapy initiation; (v) absence of a multiple primary cancer diagnosis at the time of initiating first-line therapy; (vi) no evidence of IO treatment in Stage 3 (A, B, or C) NSCLC as part of neoadjuvant or adjuvant treatment; (vii) no evidence of targetable genetic alterations (eg, EGFR , ALK , ROS1 ); and (viii) received first-line treatment with an anti–PD-1/PD-L1 agent for NSCLC.

Patient selection and study cohort derived from the Patient360 NSCLC database. 1L, first line; ALK , anaplastic lymphoma kinase; EGFR , epidermal growth factor receptor; IO, immunotherapy; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; ROS1 , ROS proto-oncogene 1, receptor tyrosine kinase. a Stage 3 (3B, 3C) or neoplasm, secondary; b Stage 4, M1 or neoplasm, metastatic

Study objectives

The study objectives were to describe the demographics, clinical characteristics, and drug treatment patterns in patients with advanced NSCLC who were treated with first-line anti–PD-1/PD-L1 therapy. This was done for the overall cohort and by year of initiation of first-line therapy (2016 to 2020) and stratified by subgroups of interest that represent clinically relevant, unmet-needs populations. Additionally, clinical characteristics were stratified by first-line therapy, ie, anti–PD-1/PD-L1 monotherapy or anti–PD-1/PD-L1 therapy combined with platinum-based chemotherapy.

Ethical considerations

The study was performed in accordance with the Declaration of Helsinki and relevant International Council for Harmonisation, Good Clinical Practice, and Good Pharmacoepidemiological Practice guidelines. As no identifiable protected health information was extracted or accessed for the conduct of this study, ethics approval was deemed unnecessary under the Code of Federal Regulations Title 45, Part 46, Section 46.104(d)(4)(ii) (45CFR46.104[d][4][ii]).

Statistical analysis

This was an observational, descriptive cohort study of real-world patients with advanced NSCLC; hence, no hypothesis was tested, and no formal sample size calculation was required. Study measures (ie, patient demographics, disease and clinical characteristics, recorded treatment) were summarized with descriptive statistics and presented as frequencies and percentages. Statistical analyses were conducted using the Palantir Foundry implementation of PySpark.

Cohort disposition

From an initial population of 26,361 curated patients available in the NSCLC database, 3886 patients met all criteria and were started on first-line therapy in the study period, and 2175 of these were treated with an anti–PD-1/PD-L1 agent in the first line during the specified period and were included in the study cohort (Fig. 2 ).

• Patient characteristics

Baseline demographics and clinical characteristics of the patients in the study cohort ( n = 2175) are summarized in Table 1 , overall and by year of first-line therapy initiation. In this eligible population, the median age was 68.0 years (range, 19.0 to 88.0 years), and 53.7% were male. The age group distribution of the cohort remained constant from 2016 to 2020. Most patients were White (76.8%); African Americans comprised the second largest racial group (13.2%). Current or former smokers made up 87.9% of study patients, with the proportion increasing from 83.3% of those who initiated first-line therapy in 2016 to 92.9% of those who initiated first-line therapy in 2020.

Approximately two-thirds of patients (66.4%) had nonsquamous NSCLC with adenocarcinoma histology (Table 1 ). Nearly all patients (96.4%) had Stage 4 disease, and 95.7% had one or more metastatic sites. Bone (29.8%), brain (22.9%), and other lung (19.9%) were the most common metastatic sites at the index date. More patients younger than 65 years (29.3%) had evidence of brain metastases than those aged 65–74 years (21.7%) and ≥75 years (15.1%) (Table 2 ). More than three-quarters (78.9%) of patients had visceral site(s) of metastases at the index date, and 37.6% had nonvisceral site(s) of metastases (Table 1 ). Almost two-thirds of patients (64.7%) with reported Eastern Cooperative Oncology Group performance status (ECOG PS) had a score of 0 or 1, and 19.8% had a score of 2 or higher.

Only one-quarter (24.4%) of patients had recorded evidence of receiving a second line of therapy (Table 1 ). Of those with first-line therapy starting in 2016–2017, only 31.6% received a subsequent, second line of therapy in the study period. Among patients with first-line therapy starting between 2018 and 2020, 22.4% had subsequent treatment with a second line of therapy in the study interval.

Most patients (89.0%) were not immunocompromised, defined as having human immunodeficiency virus (HIV) or taking long-term (≥30 days) immunosuppressive medications, at the index date. Nearly all patients had a negative history of HIV, hepatitis B and C, and autoimmune disease at the index date (99.8%, 100.0%, and 98.5%, respectively). A higher percentage of female patients used immunosuppressive medication at the index date compared with male patients (20.1% versus 15.7%) (data not shown). Use of immunosuppressive medication at the index date decreased each year, with initial use at 25.5% of patients in 2016, down to 13.5% in 2020.

Overall, only 60.1% of study patients had evidence of testing for RET- , BRAF- , or MET -targetable genetic alterations, and 8.2% of all patients had one or more positive test results (Table 1 ). More patients who initiated first-line therapy between 2018 and 2020 had evidence of testing (64.2%) than those who initiated first-line therapy from 2016 to 2017 (45.6%). Almost three-quarters (72.0%) of study patients had a PD-1/PD-L1 expression test recorded, and 45.0% of study patients had a qualitative positive test result recorded. However, only 18.1% of patients with a positive PD-1/PD-L1 test had a result reported numerically. The proportion of patients tested for PD-1/PD-L1 expression increased from 53.9% in 2016 to 79.2% in 2020, and the proportion of study patients who had a positive result increased from 33.3% to 47.2% over the same period.

Treatment patterns

Of the 2175 study cohort patients, 102 initiated first-line therapy in 2016, 376 in 2017, 586 in 2018, 717 in 2019, and 394 in 2020. First-line treatment patterns are summarized in Fig. 3 .

Treatment patterns overall and stratified by year of first-line therapy initiation. The graph shows the numbers of patients who received the treatments indicated in the legend. The table shows the numbers and percentages of patients who received each treatment regimen, along with proportions of patients receiving different types of anti–PD-1/PD-L1 monotherapy, pembrolizumab plus platinum-based chemotherapy, and nivolumab plus ipilimumab, which are shown below the relevant regimen category. During 2020, the COVID-19 pandemic may have impacted routine clinical care. Percentages reported for subcategories are proportions in the respective category, not the whole. CT, chemotherapy; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1

The most common first-line treatment overall was anti–PD-1/PD-L1 monotherapy (in 50.7% of 2175 patients), followed by anti–PD-1/PD-L1 therapy in combination with a platinum-based chemotherapy (45.5%) and anti–PD-1/PD-L1 therapy in combination with any other therapy (3.8%) (Fig. 3 ). The proportion of patients initiating first-line treatment with anti–PD-1/PD-L1 monotherapy decreased from 90.2% of the 102 patients in 2016 to 32.2% of the 394 patients in 2020, while the proportion of patients initiating first-line anti–PD-1/PD-L1 combined with platinum-based chemotherapy increased from 6.9% to 60.2%. PD-1/PD-L1 expression levels influence treatment selection, and PD-1/PD-L1 expression data was limited at the time of the data cutoff.

Most patients who initiated treatment with an anti–PD-1/PD-L1 monotherapy in this study cohort received pembrolizumab (70.2% of the 1103 patients who received monotherapy), followed by nivolumab (24.6%), then atezolizumab (5.3%) (Fig. 3 ). Use of pembrolizumab increased from 29.3% of the 92 patients treated with anti–PD-1/PD-L1 monotherapy in 2016 to 91.3% of the 127 monotherapy-treated patients in 2020, whereas the use of nivolumab declined from 65.2% in 2016 to 6.3% in 2020. Pembrolizumab was consistently the most commonly used anti–PD-1/PD-L1 mono-therapy across patient subgroups including age group, sex, number of metastatic sites, evidence of brain metastasis, ECOG PS, smoking status, and immunocompromised status (Table 3 ). It was the most common anti–PD-1/PD-L1 monotherapy, having been administered to 73.2% of 691 patients with nonsquamous and 61.4% of 267 patients with squamous NSCLC histology.

Pembrolizumab combined with platinum-based chemo-therapy was the most common combination regimen, accounting for 96.1% of the 989 study cohort patients who initiated first-line treatment with anti–PD-1/PD-L1 therapy combined with platinum-based chemotherapy (Fig. 3 ). Of the 83 patients (3.8% of the cohort) who initiated first-line treatment with anti–PD-1/PD-L1 therapy in combination with any other therapy, 56.6% received nivolumab plus ipilimumab.

From 2018 to 2020, the most common first-line treatment among patients younger than 65 years was anti–PD-1/PD-L1 in combination with platinum-based chemotherapy (61.1%); and in those 75 years or older, the most common regimen was anti–PD-1/PD-L1 monotherapy (56.7%) (data not shown). During the same period, 55.3% of patients with nonsquamous NSCLC were treated with anti–PD-1/PD-L1 in combination with platinum-based chemotherapy, and 40.8% received anti–PD-1/PD-L1 monotherapy (data not shown). The proportions of patients with 1, 2, or ≥3 metastatic sites treated with anti–PD-1/PD-L1 in combination with platinum-based chemotherapy were 50.9%, 54.6%, and 64.7%, respectively (data not shown). From 2018 to 2020, anti–PD-1/PD-L1 in combination with platinum-based chemotherapy was also the most commonly used regimen in patients with ECOG PS 0 or 1 (55.5%), current or former smokers (53.6%), and those who were not immunocompromised (53.9%) (data not shown).

This retrospective, real-world cohort study using the ConcertAI Patient360 NSCLC database demonstrated that, from 2016 to 2020, the most common first-line treatment among US patients with locally advanced or metastatic NSCLC who received IO treatment was anti–PD-1/PD-L1 monotherapy, followed by anti–PD-1/PD-L1 agents combined with platinum-based chemotherapy. Nivolumab was the most common monotherapy in 2016, but after the negative CheckMate-026 trial, was overtaken by pembrolizumab in 2017, which remained the most frequently used monotherapy agent until the end of the study period in 2020, corresponding with the positive KEYNOTE-024 trial results [ 15 , 20 ]. A shift in the most commonly used treatments occurred during the study period, from predominantly anti–PD-1/PD-L1 monotherapy in 2016 to combination treatment with anti–PD-1/PD-L1 agents and platinum-based chemotherapy. This was likely driven by US regulatory approval of IO-chemotherapy combination regimens and positive clinical trial results after earlier approvals of IO monotherapies [ 21 , 22 , 23 , 24 , 25 ].

Several patient characteristics in this real-world cohort differed from those in pivotal IO clinical trials [ 5 , 9 , 11 , 12 ]. The median age of 68.0 years was numerically higher than the median of approximately 60–65 years in several clinical trials [ 5 , 9 , 11 , 12 , 26 ], and 26.2% of the patients in this study were 75 years or older. This finding is consistent with another real-world study [ 26 ], which demonstrated that patients receiving IO in the clinic are substantially older than patients studied in the trials that led to these agents’ approvals, as NSCLC trials often recruit fewer elderly patients [ 26 ]. Clinical trials also typically exclude patients with ECOG PS >1, but almost 20% of the patients in this study had ECOG PS ≥2. In our study, ECOG PS deteriorated with age, suggesting that including greater proportions of elderly patients may make clinical trials substantially more generalizable to the real-world setting. Compared with real‑world studies of patients receiving first-line treatment for metastatic NSCLC [ 18 , 27 ], our study included a higher proportion of patients with an ECOG score ≥2 and a higher proportion of patients with brain metastases.

Patients with a history of autoimmune disease and those who are immunocompromised or receiving immuno-suppressive medications are also generally excluded from clinical trials of IO, but these types of patients comprised 1.5%, 11.0%, and 17.7%, respectively, of this real-world cohort and received first-line IO therapy for NSCLC. The fact that 78.9% of this study cohort had visceral metastases and 37.6% had nonvisceral metastases suggests that a substantial proportion of this cohort had dual visceral and nonvisceral metastases.

This study has several strengths and limitations. The database provided valuable real-world data on diagnosis, clinical assessment, and recorded treatments in patient groups not typically enrolled in clinical trials, such as older patients and those with higher ECOG PS, immuno-suppression, and various types and numbers of metastatic sites.

This was a descriptive observational study (no hypothesis testing) and has several limitations. The study may have been subject to confounding if physicians preferentially prescribed certain therapies to patients who were perceived to have worse adverse effects if their underlying disease was more severe or if they had poorer overall health. The study was not designed to evaluate patient outcomes; therefore, no conclusions on prognosis may be drawn. As with all retrospective epidemiological studies, unmeasured confounding and missing data may have an impact on the descriptive estimates presented.

Data entry errors at the points of care could not be detected nor corrected during analysis. Missing data in the form of information not routinely and repeatedly captured may also have impacted the completeness, validity, and reliability of some variables (eg, PD-L1 testing). Potentially interesting data that were unavailable for analysis included the rate of transition to second-line treatment when stratified by first-line therapy and information on local radiotherapy. This study included patients who were treated during the COVID-19 pandemic, which may have impacted routine clinical care in the year 2020. Finally, patients treated at individual sites included in this study may not be representative of all patients with NSCLC across all the sites of care in the US. This study highlights the differences in patient characteristics between real-world populations and clinical trial populations, presenting difficulties in treating patients underrepresented in clinical trial populations. Incorporating more diverse, traditionally excluded patient populations will increase the generalizability of studies and provide the evidence-base required to support decision-making in routine clinical practice.

Conclusions

The initial adoption of anti–PD-1/PD-L1 monotherapy as first-line treatment for advanced NSCLC in the US quickly shifted to combination anti–PD-1/PD-L1 therapy with platinum-based chemotherapy between 2016 and 2020. This real-world study was conducted during these important inflection points for the treatment of advanced NSCLC with anti–PD-1/PD-L1 therapy. This study has emphasized the real-world patient characteristics, how they differ from clinical trial populations, and how these characteristics impact treatment patterns.

In conclusion, we have shown that evidence gaps exist for patients who are older, have ECOG PS ≥2, and are on immunosuppressive medications—patients who make up a substantial proportion of real-world patient populations. To optimize the personalized treatment of advanced NSCLC, further real-world studies will be needed to elucidate the clinical characteristics of patients with advanced NSCLC who are most likely to benefit from an evolving first-line IO treatment landscape.

Availability of data and materials

The data that support the findings of this study are available from ConcertAI but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. The corresponding author may be contacted regarding potential access to the data upon reasonable request and with permission of ConcertAI.

Abbreviations

Anaplastic lymphoma kinase

Proto-oncogene B-Raf

Chemotherapy

Cytotoxic T lymphocyte-associated antigen 4

Eastern Cooperative Oncology Group performance status

Epidermal growth factor receptor

Electronic medical record

Food and Drug Administration

Human immunodeficiency virus

Immunotherapy

Mesenchymal epithelial transition factor

Not otherwise specified

• Non-small cell lung cancer

Programmed cell death protein 1

Programmed cell death ligand 1

RET proto-oncogene

ROS proto-oncogene 1

United States

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660 .

Article   CAS   PubMed   Google Scholar  

Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94. https://doi.org/10.4065/83.5.584 .

Article   PubMed   Google Scholar  

Jones CM, Brunelli A, Callister ME, Franks KN. Multimodality treatment of advanced non-small cell lung cancer: where are we with the evidence? Curr Surg Rep. 2018;6(2):5. https://doi.org/10.1007/s40137-018-0202-0 .

Article   PubMed   PubMed Central   Google Scholar  

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–50. https://doi.org/10.1056/NEJMoa1809697 .

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. https://doi.org/10.1056/NEJMoa1716948 .

Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592–604. https://doi.org/10.1016/S0140-6736(21)00228-2 .

Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, et al. Nivolumab versus docetaxel in previously treated patients with advanced non–small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017;35(35):3924–33. https://doi.org/10.1200/jco.2017.74.3062 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic non-squamous non–small-cell lung cancer. J Clin Oncol. 2020;38(14):1505–17. https://doi.org/10.1200/jco.19.03136 .

Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. https://doi.org/10.1056/NEJMoa1910231 .

Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–30. https://doi.org/10.1016/s0140-6736(18)32409-7 .

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non–small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%. J Clin Oncol. 2021;39(21):2339–49. https://doi.org/10.1200/jco.21.00174 .

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65. https://doi.org/10.1016/s0140-6736(16)32517-x .

Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. https://doi.org/10.1016/s0140-6736(16)00587-0 .

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643 .

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774 .

Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82. https://doi.org/10.1200/JCO.2014.59.4358 .

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. v1.2022 - December 7, 2021. 2021. https://www.nccn.org/patientresources/patient-resources/guidelines-for-patients . Accessed 25 Jan 2022.

Velcheti V, Hu X, Piperdi B, Burke T. Real-world outcomes of first-line pembrolizumab plus pemetrexed-carboplatin for metastatic nonsquamous NSCLC at US oncology practices. Sci Rep. 2021;11(1):9222. https://doi.org/10.1038/s41598-021-88453-8 .

FDA approval timeline of active immunotherapies. https://www.cancerresearch.org/regulatory-approval-timeline-of-active-immunotherapies . Accessed 20 Apr 2023.

Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–26. https://doi.org/10.1056/NEJMoa1613493 .

FDA approves Genentech’s Tecentriq in combination with Avastin and chemotherapy for the initial treatment of metastatic non-squamous non-small cell lung cancer. 2018. https://www.drugs.com/newdrugs/fda-approves-genentech-s-tecentriq-combination-avastin-chemotherapy-initial-metastatic-non-squamous-4883.html . Accessed 28 Mar 2022.

FDA approves Opdivo (nivolumab) + Yervoy (ipilimumab) as first-line treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1≥1%. 2020. https://www.drugs.com/newdrugs/fda-approves-opdivo-nivolumab-yervoy-ipilimumab-first-line-patients-metastatic-non-small-cell-lung-5239.html . Accessed 28 Mar 2022.

FDA approves Genentech’s Tecentriq plus chemotherapy (Abraxane and carboplatin) for the initial treatment of metastatic non-squamous non-small cell lung cancer. 2019. https://www.drugs.com/newdrugs/fda-approves-genentech-s-tecentriq-plus-chemotherapy-abraxane-carboplatin-initial-metastatic-non-5117.html . Accessed 28 Mar 2022.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. https://doi.org/10.1056/NEJMoa1801005 .

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–51. https://doi.org/10.1056/NEJMoa1810865 .

O’Connor JM, Fessele KL, Steiner J, Seidl-Rathkopf K, Carson KR, Nussbaum NC, et al. Speed of adoption of immune checkpoint inhibitors of programmed cell death 1 protein and comparison of patient ages in clinical practice vs pivotal clinical trials. JAMA Oncol. 2018;4(8):e180798. https://doi.org/10.1001/jamaoncol.2018.0798 .

Simeone JC, Nordstrom BL, Patel K, Klein AB. Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting. Future Oncol. 2019;15(30):3491–502. https://doi.org/10.2217/fon-2019-0348 .

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Acknowledgements

Samantha Santangelo and Micaela Genca provided medical writing support on behalf of inScience Communications (Philadelphia, PA). This work was performed in accordance with current Good Publication Practice guidelines, and was funded by Sanofi, Inc.

This work was supported by Sanofi, which was involved in the study design; data analysis and interpretation; manuscript writing; and the decision to submit to BMC Cancer .

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H.A.D. provided conceptualization, methodology, data curation, formal analysis, and writing of the manuscript. M.A.B. provided data curation, formal analysis, and writing of the manuscript. A.K. provided conceptualization, methodology, data curation, writing, and supervision of the manuscript. D.P.C. provided conceptualization, methodology, writing, and supervision of the manuscript.

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Correspondence to Ashok Krishna .

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The study was performed in accordance with the Declaration of Helsinki and relevant International Council for Harmonisation, Good Clinical Practice, and Good Pharmacoepidemiological Practice guidelines. As no identifiable protected health information was extracted or accessed for the conduct of this study, ethics approval and informed consent were deemed unnecessary under the Code of Federal Regulations Title 45, Part 46, Section 46.104(d)(4)(ii) (45CFR46.104[d][4][ii]).

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H.A.D. was an employee of Sanofi at the time of the study and holds stock in the company. M.A.B. received consulting fees from Sanofi. A.K. is an employee of Sanofi and holds stock in the company. D.P.C. has received funding from clinical trial grants from Genentech and Merck Sharp & Dohme to The Ohio State University; received consulting fees from Bristol Myers Squibb (BMS), BMS KK, Boehringer Ingelheim, Curio Science, Genentech/Roche, GI Therapeutics (Intellisphere), GlaxoSmithKline (GSK), Janssen, Mirati, Novartis, Novacure, OncoCyte, OncoHost, Roche China, and Seattle Genetics; received honoraria from AstraZeneca and BMS; participated in Data Safety Monitoring Boards for European Organisation for Research and Treatment of Cancer (EORTC), AbbVie, and Lilly; and participated in advisory boards for Amgen, Arcus Biosciences, AstraZeneca, Cantargia, Daiichi Sankyo, EMD Serono/Merck, Flame Biosciences, Gritstone Oncology, GSK, Lilly, Regeneron, Sanofi, and Seattle Genetics.

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Divan, H.A., Bittoni, M.A., Krishna, A. et al. Real-world patient characteristics and treatment patterns in US patients with advanced non-small cell lung cancer. BMC Cancer 24 , 424 (2024). https://doi.org/10.1186/s12885-024-12126-8

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Recognising Lung Cancer in Primary Care

Stephen h. bradley.

1 Academic Unit of Primary Care, University of Leeds, Leeds, UK

Martyn P. T. Kennedy

2 Department of Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK

Richard D. Neal

Significant advances in the management of both early and advanced stage lung cancer have not yet led to the scale of improved outcomes which have been achieved in other cancers over the last 40 years. Diagnosis of lung cancer at the earliest stage of disease is strongly associated with improved survival. Therefore, although recent advances in oncology may herald breakthroughs in effective treatment, achieving early diagnosis will remain crucial to obtaining optimal outcomes. This is challenging, as most lung cancer symptoms are non-specific or are common respiratory symptoms which usually represent benign disease. Identification of patients at risk of lung cancer who require further investigation is an important responsibility for general practitioners (GPs). Diagnosis has historically relied upon plain chest X-ray (CXR), organised in response to symptoms. The sensitivity of this modality, however, compares unfavourably with that of computed tomography (CT). In some jurisdictions screening high-risk individuals with low dose CT (LDCT) is now recommended. However uptake remains low and the eligibility for screening programmes is restricted. Therefore, even if screening is widely adopted, most patients will continue to be diagnosed after presenting with symptoms. Achieving early diagnosis requires GPs to maintain an appropriate level of suspicion and readiness to investigate in high-risk patients or those with non-resolving symptoms. This article discusses the early detection of lung cancer from a primary care perspective. We outline risk factors and epidemiology, the role of screening and offer guidance on the recognition of symptomatic presentation and the investigation and referral of suspected lung cancer.

Introduction

Lung cancer is a primary cancer of the lung and is classified histologically as small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). The most common histological subtypes of NSCLC are adenocarcinoma, squamous cell and large cell cancers.

Excluding non-melanoma skin cancers, lung cancer is the both the commonest type of cancer worldwide and the single largest cause of cancer mortality [ 1 ]. In England, lung cancer accounts for 13% of all cancers, following only breast and prostate cancer in terms of incidence [ 2 ], but is the leading cause of cancer deaths [ 3 ].

Improvements in early diagnosis and treatment have led to improved outcomes for many cancers. Since 1971, age-standardised 5-year survivals from breast cancer, prostate cancer and colorectal cancer in England and Wales have increased from 53% to 87% [ 4 ], 37% to 85% [ 5 ] and 24% to 59% respectively [ 6 ]. In contrast, the age-standardised 5-year survival for lung cancer has only increased from 5% to 10% [ 7 ]. Advances in the systemic treatment of advanced lung cancer with the use of tyrosine kinase inhibitors (TKIs) and immunotherapy have led to significant survival benefits for some patients [ 8 – 10 ]. The relatively infrequent expression of targets for these treatments and poor prognosis associated with advanced lung cancer have prevented these advances significantly impacting on overall survival. The introduction of stereotactic radiotherapy (SABR) has increased the radical treatment rate for early stage lung cancer without reducing surgical resection rates [ 11 ]. Lung cancer outcomes differ according to stage at diagnosis, with a 1-year survival of 81.7% for stage I and 15.5% for stage IV lung cancer in England and Wales [ 12 ]. Therefore, despite the substantial promise offered by novel therapies, achieving early diagnosis is likely to remain a crucial part of improving outcomes.

Most patients with lung cancer first present to their general practitioner (GP) [ 13 – 16 ]. Lung cancer often presents with symptoms that are very commonly encountered in primary care, making early diagnosis challenging. A large UK-based population study demonstrated that although cough is one of the most frequent symptoms of lung cancer, only 0.2% of patients who had a cough for 3 weeks were ultimately diagnosed with lung cancer [ 17 ]. The UK’s National Cancer Diagnosis Audit reported that the median primary care interval (time from first presentation to referral) for lung cancer was 14 days, the second highest of 15 cancers reported. Prolonged primary care intervals of 60 and 90 days were experienced by 17.9% and 10.8% of patients respectively [ 18 ]. A third of patients diagnosed with lung cancer have attended their GP with symptoms attributable to their cancer three or more times before diagnosis [ 19 ]. Unfortunately, most lung cancers are still diagnosed at an advanced stage [ 20 ] and a third of lung cancers are diagnosed during emergency presentations [ 21 ]. The priority for most of these patients will be for prompt referral and investigation. Some patients with a high probability of malignant disease presenting with significant symptom burdens, rapid clinical deterioration or a high risk of acute hospital admission may benefit from synchronous referral to community palliative care services.

In common with other cancers, system factors are likely to affect the promptness of diagnosis. Some evidence suggests that settings that permit greater access to investigations are associated with improved survival [ 22 ]. Systems in which primary care practitioners have a strong role in rationing access to secondary care have been associated with poorer survival for the ten most common cancers, including lung cancer [ 23 ]. This suggests that the gate-keeping role of primary care practitioners may be a barrier to early diagnosis. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Risk Factors and Epidemiology

Risk factors for the development of lung cancer include tobacco exposure, asbestos exposure, other occupational exposures, older age, male sex, chronic obstructive pulmonary disease (COPD), family history and air pollution.

Tobacco exposure remains the single greatest risk factor for developing lung cancer. In the UK, an estimated 71% of lung cancer deaths have been attributed to smoking and an additional 1% to environmental tobacco smoke (‘second-hand smoke’ or ‘passive smoking’) [ 24 ]. A Canadian study determined lifetime risks of lung cancer as 17.2% and 11.6% for male and female smokers respectively, compared to 1.3% and 1.4% for never-smokers [ 25 ]. The risk is increased by both the total quantity of tobacco to which an individual is exposed and the duration of time of which an individual remains a smoker [ 26 ]. The relative risk of lung cancer death is approximately 15 times higher in smokers compared to never-smokers, as demonstrated in a seminal cohort study [ 27 ]. Upon stopping smoking the relative risk of developing lung cancer declines rapidly; however, ex-smokers remain at an elevated level of risk compared to never-smokers [ 28 ].

Despite the well-understood link between smoking and lung cancer, clinicians should remain mindful that a significant proportion of lung cancers occur in patients who have never smoked, estimated at between 10% and 15% in one North American study [ 29 ].

Evidence of airway obstruction, typically associated with chronic obstructive pulmonary disease (COPD) and emphysema, is an independent risk factor for developing lung cancer, with a relative risk at least double that of matched populations without airway obstruction [ 30 – 32 ]. This remains significant even when factors such as over diagnosis of COPD are taken into account [ 33 ]. COPD and lung cancer have therefore been characterised as linked diseases, possibly sharing common pathological mechanisms [ 34 ].

After smoking, the working environment is the next most significant risk factor with 13% of lung cancers in the UK attributed to occupational exposures [ 24 ]. Asbestos accounts for a large proportion of these cases [ 35 ], though other occupational carcinogens include silica (e.g. through glass manufacture and sand-blasting processes in textile manufacturing), diesel engine exhaust and aerosols inhaled whilst painting and welding [ 36 ]. Meanwhile, a further 8% of UK lung cancer cases have been attributed to air pollution [ 24 ].

While there are clear associations between these environmental and demographic factors and the incidence of lung cancer, it is important to recognise that lung cancer does still occur in younger patients and never-smokers. There is an increased prevalence of driver mutations, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in patients with lung cancer who are younger and those who have never smoked. These driver mutations predict response to TKI therapy, which can lead to improved survival in patients with advanced disease [ 9 , 10 ].

Lung cancer remains more common amongst men than women in the UK, with crude incidences of 77 and 66 per 100,000 population [ 37 ]. This is likely to be mediated strongly by differences in smoking behaviours, with 21.1% of males and 16.5% of females in the UK smoking in 2013 [ 38 ]. The incidence of lung cancer amongst men is declining globally, but is increasing amongst women in high income countries, reflecting patterns of increasing tobacco use in women and declining use in men [ 39 ].

Genetic factors play a role in the development of lung cancer [ 40 ] with a meta-analysis indicating that risk is 82% higher in those in whom a sibling has been diagnosed with lung cancer, after adjustment for smoking and other potential confounders [ 41 ].

Lung cancer incidence increases with age [ 42 ] and the median age of diagnosis in England and Wales was 72 years for women and 73 years for men in 2016 [ 12 ]. Although lung cancer is rare under the age of 40, clinicians should not dismiss the possibility of lung cancer in younger patients.

Symptoms and Signs

The referral recommendations from the National Institute for Health and Care Excellence (NICE) are outlined in Box 1 [ 43 ]. This guidance was updated in 2015 with new recommendations that GPs refer all patients over age 40 years with unexplained haemoptysis and that consideration be given to plain chest X-ray (CXR) for patients with thrombocytosis and/or appetite loss.

Box 1: Recommendations from NICE guideline [NG12] suspected cancer: recognition and referral [ 43 ]

Refer people using a suspected cancer pathway referral (for appointment within 2 weeks) for lung cancer if they:

• Have chest X-ray findings that suggest lung cancer or
• Are aged 40 and over with unexplained haemoptysis

Offer an urgent chest X-ray (to be performed within 2 weeks) to assess for lung cancer in people aged 40 and over if they have 2 or more of the following unexplained symptoms, or if they have ever smoked and have 1 or more of the following unexplained symptoms:

• Shortness of breath
• Weight loss
• Appetite loss

Consider an urgent chest X-ray (to be performed within 2 weeks) to assess for lung cancer in people aged 40 and over with any of the following:

• Persistent or recurrent chest infection
• Finger clubbing
• Supraclavicular lymphadenopathy or persistent cervical lymphadenopathy
• Chest signs consistent with lung cancer
• Thrombocytosis

The earliest stage of lung cancer is often not associated with any symptoms. The most common symptoms associated with lung cancer tend to be both common in benign presentations in the community and particularly amongst smokers. Therefore the discriminative utility of most of these symptoms in isolation is low. Positive predictive values (PPVs) for different symptoms of lung cancer, both alone and in combination, have been determined from a case–control study and are presented in Fig.  1 . Importantly PPVs for each symptom are higher in smokers and those over the age of 70 years [ 44 ]. With the highest PPV of 2.4–7.5% [ 45 ], unexplained haemoptysis always warrants further investigation. Haemoptysis, however, is a feature of only about a fifth of lung cancers [ 46 , 47 ], so the absence of this symptom should not provide reassurance.

Positive predictive values (%) for lung cancer for individual risk markers, and for pairs of risk markers in combination (against a background risk of 0.18%). (1) The top row (bold) gives the PPV for an individual feature. The cells along the diagonal relate to the PPV when the same feature has been reported twice. Other cells show the PPV when a patient has two different features. (2) The top figure in each cell is the PPV. It has only been calculated when a minimum of ten cases had the feature or combination of features. The two other figures are the 95% CIs for the PPV. These have not been calculated when any cell in the 2 × 2 table was below 10. (3) The yellow shading is when the PPV is above 1%. The amber shading is when the PPV is above 2%. The red shading is for PPVs above 5.0%.

Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature. Ref. [ 54 ]

While guidelines have streamlined access to diagnosis for some, concern has been raised that this approach might prioritise patients with classical presentations, such as haemoptysis, at the expense of those with symptoms which reflect less advanced disease and would therefore have the most to gain from early diagnosis [ 13 ]. In fact, in 2013 only 28% of lung cancer cases in England were diagnosed through the country’s ‘2-week-wait’ urgent referral pathway. In many cases appropriately urgent action may have occurred outside the 2-week-wait pathway, for example through automatic referral following a suspicious CXR or through routine surveillance for pulmonary nodules. Although declining as a proportion, diagnoses following emergency presentations remained the commonest route of diagnosis at 35% [ 48 ]. Such diagnoses are associated with the poorest outcomes, although the reasons for this are likely to be complex and probably include the poorer performance status, more advanced disease and greater levels of socio-economic deprivation of patients who present in this way [ 49 ].

In order to reduce the time intervals between patients experiencing symptoms and presenting to their GP, significant efforts have been made to improve public awareness. Evaluations of England’s ‘Be Clear on Cancer’ campaign have suggested the programme contributed to encouraging increases in presentations to primary care with prolonged cough and an increase in the proportions diagnosed with early stage lung cancer [ 50 , 51 ]. A longer-term assessment, however, has suggested that such campaigns require sustained commitment in order to maximise their impact [ 52 ]. In Australia, a cluster randomised trial of a complex intervention which included a public awareness campaign showed no reduction in the interval between symptoms and diagnosis [ 53 ], although the authors speculate that the intervention may not have achieved the breadth of media coverage required to show an effect.

A simple risk assessment tool has been developed which can generate positive predictive values for one symptom or two symptoms in combination stratified for smokers and non-smokers [ 54 ]. Assessment of this tool (Fig.  1 ) has shown that, when used, it is associated with increased investigations such as CXR, urgent referrals and lung cancer diagnoses [ 55 ]. Two algorithms have also been created which incorporate symptoms as well as other risk factors to generate risk scores [ 17 , 56 ].

Positive examination findings are usually only associated with advanced disease, so examination will typically be unremarkable. Since an individual GP will, on average, encounter only one new case of lung cancer each year [ 57 ], the prospects of identifying lung cancer through rare signs such as hypertrophic pulmonary osteoarthropathy and Horner’s syndrome are exceedingly unlikely. In clinical practice, patient and physician intuition of the possibility of serious underlying disease is probably much more important [ 58 ]. Given that the ‘risk threshold’ NICE has adopted for further investigation or referral for suspected cancer is 3% [ 43 ], GPs should feel empowered to refer patients at relatively low levels of risk [ 59 ].

In situations in which a decision for further follow-up or investigation has not been made, GPs should advise their patients to represent if symptoms fail to resolve or new symptoms develop. Although little evidence exists for the effectiveness of ‘safety netting’ [ 60 ], the experience of significant event audit suggests it is an important strategy to reduce the risk of delayed diagnosis [ 61 ]. Safety netting is recommended as part of the NICE guidelines for suspected cancer referral [ 43 ] and GPs should be aware that there is a medico-legal expectation that safety netting is adequately undertaken and documented [ 62 ].

Investigation of Suspected Lung Cancer

The first-line investigation of suspected lung cancer remains the CXR. CXR has the advantages of being cheap and accessible [ 58 ], with a low radiation dose of 0.02 mSv equivalent to 3 days of natural background radiation [ 63 ]. Unfortunately, CXR has a significant false negative rate, with a sensitivity of approximately 75–80% [ 64 – 67 ]. One study has reported that 10% of the CXRs of lung cancer patients were initially reported as normal, with a further 13% which were reported as abnormal but with no suspicion of lung cancer [ 64 ]. Despite its limitations, evidence suggests that strategies to increase CXR uptake can yield improvements in referral rates and possibly improve early detection of lung cancer [ 51 , 68 ].

Previous guidance that all patients with radiologically demonstrated community-acquired pneumonia should have a repeat CXR after 6 weeks to confirm resolution has been refined to include only those at highest risk of malignancy, such as smokers and those aged over 50 years [ 69 ]. Evidence from a population-based cohort study provides some reassurance that such an approach is reasonable, given that only one in 57 patients who did have lung cancer 1 year following their pneumonia were under the age of 50 and that overall only 40% of patients attended for a repeat CXR within 90 days [ 70 ].

Computed tomography (CT) scans of the chest are much more sensitive than CXR, although the majority of available evidence relates to screening contexts, rather than the investigation of symptomatic patients. In the US National Lung Screening Trial (NLST), low dose CT (LDCT) yielded sensitivity and specificity of 93.8% and 73.4% compared to 73.5% and 91.3% for CXR, respectively [ 71 ]. In most contexts conventional CT continues to be used for symptomatic investigation. NICE recommends contrast-enhanced CT of the thorax including also the liver and adrenal glands [ 72 ]. This is usually arranged from secondary care following an urgent referral from a primary care physician for suspected lung cancer, although in some regions GPs may have direct access to CT. In the UK the National Optimal Lung Pathway [ 73 ] has set out standards for lung cancer service providers to improve the quality and efficiency of pathways for patients with suspected lung cancer including the timing of investigations. This pathway aims to reduce the time between referral, CT scan and review by respiratory physician with an interest in lung cancer.

Access to and use of CT varies greatly across different health systems. Fewer CT scans are performed in the UK than other Western European countries [ 74 ]. Higher rates of CT use in the US have been identified as a concern given the resulting radiation exposure [ 75 ]. LDCT uses an estimated radiation dose of 2 mSv, compared to 7 mSv from conventional CT [ 76 ]. Increased availability of LDCT in the future could help reduce the total radiation exposure.

Widening access to urgent CT scans for GPs (sometimes termed ‘direct access’) has been suggested as a means to improve early stage diagnosis [ 77 ]. In Denmark, a country where GPs serve a similar gate-keeping role to their counterparts in the UK, a cluster-randomised controlled trial found that giving GPs access to LDCT to investigate possible lung cancer led to no statistically significant decrease to the time to diagnosis. Following adjustment for non-engagement in the intervention group it was found that patients in the control group were at a higher risk of experiencing a long diagnostic interval [ 78 ]. The relatively low levels of engagement, which reached only around half of eligible GPs, might suggest that achieving uptake of direct access investigations requires a broader shift in practice rather than simply permitting their use.

Patients with haemoptysis have also routinely been investigated with bronchoscopy to exclude lung cancer. Diagnostic evaluations of CT have suggested that bronchoscopy can be omitted in most cases if malignancy is not identified on CT [ 79 , 80 ].

The US Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial has provided the largest and most conclusive body of evidence that screening asymptomatic populations with CXR does not reduce lung cancer mortality [ 81 ]. The US National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer mortality with annual LDCT in an asymptomatic high-risk population [ 82 ]. The US Preventative Task Force (USPSTF) has since recommended annual screening with LDCT for those aged 55–80 who have a 30-pack-year smoking history and are current smokers or have smoked within the last 15 year [ 83 ]. Uptake of screening in the USA, however, remains low [ 84 , 85 ]. This may be due to the lack of a fully co-ordinated national approach [ 86 ]. The European Union position statement on lung cancer screening set out specific actions that were required before the widespread implementation of lung cancer screening [ 87 ]. The UK National Screening Committee (NSC) does not currently recommend lung cancer screening. The NSC is expected to review this decision following the publication of final results from the Dutch-Belgian NELSON trial [ 88 ]. These results were presented at the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung cancer (WCLC) 2018 in Toronto. The presented data demonstrated a significant reduction in lung cancer mortality in the screened male population. There was a greater reduction in mortality in the screened female population, but this cohort was smaller and this difference did not reach significance. Combined population data and overall mortality data has not yet been presented.

Potential harms of LDCT screening must be weighed against any potential benefits. These include increased exposure to ionising radiation [ 89 ], invasive investigation and follow-up for benign changes and over diagnosis of cancers which if left undiscovered would not have affected patients [ 90 – 93 ]. The experience of the Danish Lung Cancer screening trial suggests that the problem of overdiagnosis in particular could be greater than that previously estimated in the National Lung Cancer Screening Trial [ 94 ]. Unfortunately, evidence from the USA suggests that in discussing lung cancer screening, clinicians’ communication of the possible harms is very limited [ 95 ]. These harms are reduced by targeting screening programmes on the population at highest risk of lung cancer.

Analysis of the Surveillance, Epidemiology and End Results (SEER) database has shown that only 26.7% of patients with lung cancer in the USA would have been eligible for LDCT screening by NLST criteria [ 96 ]. The use of composite risk prediction tools, such as The Liverpool Lung Project [ 97 ] or PLCO M2012 models [ 98 ], may better identify the high-risk population and increase the proportion of lung cancers that may be detected by screening. A significant proportion of patients who go on to develop lung cancer will not have been eligible for LDCT screening. Of those who are eligible, some will choose not to undergo screening and the possibility remains of developing lung cancer between annual LDCT screening (interval cancers). It is therefore likely that the majority of lung cancers will continue to be diagnosed by appropriate investigation of symptomatic patients by vigilant clinicians.

Conclusions

Improving early diagnosis of lung cancer is crucial to improving outcomes. The majority of patients with lung cancer present to their GP with symptoms and the early identification of lung cancer remains a key challenge. The low cost, safety and availability of CXR justify a low threshold for use of this investigation by GPs. In the context of patients with ongoing symptoms and/or significant risk factors, however, clinicians should be aware of the imperfect sensitivity of CXR and exercise appropriate vigilance. Depending on the level of risk, strategies including safety netting, planning a repeat CXR after an appropriate interval or an urgent referral for further investigation such as CT or secondary care assessment may be reasonable.

While screening with LDCT may offer improved outcomes to the highest-risk populations, most patients who develop lung cancer will not be eligible for screening meaning that the role of GPs in recognising symptomatic disease will remain crucial.

Acknowledgements

No funding or sponsorship was received for this study or publication of this article.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Stephen H. Bradley is funded by the multi-institutional CanTest Collaborative which is funded by Cancer Research UK (C8640/A23385). Richard D. Neal is an Associate Director of the multi-institutional CanTest Collaborative which is funded by Cancer Research UK (C8640/A23385). Martyn P.T. Kennedy has nothing to disclose.

Compliance with Ethical Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Enhanced digital features

To view enhanced digital features for this article go to 10.6084/m9.figshare.7334852.

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After 40 years of smoking, she survived lung cancer thanks to new treatments

Yuki Noguchi

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission. Denise Lee hide caption

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission.

Denise Lee grew up in Detroit in the mid-1970s and went to an all-girls Catholic high school. She smoked her first cigarette at age 14 at school, where cigarettes were a popular way of trying to lose weight.

Instead, her nicotine addiction lasted four decades until she quit in her mid-50s.

"At some point it got up as high as 2.5 packs a day," Lee, 62, recalls.

Yet she didn't think about lung cancer risk — until she saw a billboard urging former smokers to get screened. Lee, a retired lawyer living in Fremont, Calif., used to drive past it on her way to work.

"The thing that caught my attention was the fact that it was an African American female on the front," she recalls.

Shots - Health News

The american cancer society says more people should get screened for lung cancer.

She eventually got the low-dose CT scan recommended for current and former smokers. When doctors found an early, but dangerous, tumor, Lee cried and panicked. Her mother had cared for her father, who'd died of prostate cancer. "My biggest concern was telling my mom," she says.

But that was six years ago, and Lee is cancer free today. Surgery removed the 2-inch tumor in her lung, then new treatments also boosted her immune system, fighting off any recurrence.

Lung cancer remains the most lethal form of the disease, killing about 135,000 Americans a year – more than breast, prostate and colon cancer combined – which is why many people still think of a diagnosis as synonymous with a death sentence. But with new treatments and technology, the survival rates from lung cancer are dramatically improving, allowing some patients with relatively late-stage cancers to live for years longer.

"If you're gonna have lung cancer, now is a good time," Lee says of the advances that saved her.

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective. Denise Lee hide caption

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective.

The key breakthrough, says Robert Winn, a lung cancer specialist at Virginia Commonwealth University, is the ability to better pinpoint the mutations of a patient's particular form of cancer. In the past, treatments were blunt tools that caused lots of collateral damage to healthy parts of the body while treating cancer.

"We've gone from that to molecular characterization of your lung cancer, and it has been a game changer," Winn says. "This is where science and innovation has an impact."

One of those game-changing treatments is called targeted therapy . Scientists identify genetic biomarkers in the mutated cancer cells to target and then deliver drugs that attack those targets, shrinking tumors.

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Another is immunotherapy, usually taken as a pill, which stimulates the body's own defense system to identify foreign cells, then uses the immune system's own power to fight the cancer as if it were a virus.

As scientists identify new cancer genes, they're creating an ever-broader array of these drugs.

Combined, these treatments have helped increase national survival rates by 22% in the past five years – a rapid improvement over a relatively short time, despite the fact that screening rates are very slow to increase. Winn says as these treatments get cheaper and readily available, the benefits are even reaching rural and Black populations with historic challenges accessing health care.

The most remarkable thing about the drugs is their ability to, in some cases, reverse late-stage cancers. Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital and faculty at Harvard Medical School, recalls seeing scans where large dark shadows of tumor would disappear: "It was remarkable to see the lung cancer completely melting away."

To Yang, such progress feels personal. He lost his beloved grandfather to the disease when Yang was in college. If he were diagnosed today, he might still be alive.

"Helping to take care of him was a big reason why I wanted to be a doctor," Yang says.

But the work of combating lung cancer is far from over; further progress in lung cancer survival hinges largely on getting more people screened.

Low-dose CT scans are recommended annually for those over 50 who smoked the equivalent of a pack a day for 20 years. But nationally, only 4.5% of those eligible get those scans , compared to rates of more than 75% for mammograms.

Andrea McKee, a radiation oncologist and spokesperson for the American Lung Association, says part of the problem is that lung cancer is associated with the stigma of smoking. Patients often blame themselves for the disease, saying: "'I know I did this to myself. And so I don't I don't think I deserve to get screened.'"

McKee says that's a challenge unique to lung cancer. "And it just boggles my mind when I hear that, because, of course, nobody deserves to die of lung cancer."

Denise Lee acknowledges that fear. "I was afraid of what they would find," she admits. But she urges friends and family to get yearly scans, anyway.

"I'm just so grateful that my diagnosis was early because then I had options," she says. "I could have surgery, I could have chemotherapy, I could be a part of a clinical trial."

And all of that saved her life.

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• immunotherapy
• lung cancer

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Contemporary developments in met-selective kinase inhibitors in advanced non–small-cell lung cancer.

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• Published: 08 April 2024

Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study

• Chao Mei 1 ,
• Tian Wang 2 ,
• Baoli Xu 1 ,
• Sanlan Wu 1 ,
• Xuelin Zhang 3 ,
• Yongning Lv 1 ,
• Yu Zhang 1 ,
• Zhaoqian Liu 4 &
• Weijing Gong 1 , 5  

BMC Pulmonary Medicine volume  24 , Article number:  167 ( 2024 ) Cite this article

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Cyclin D1 ( CCND1 ) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer.

This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations.

The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057–2.912, P  = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029–3.605, P  = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428–90.100, P  = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276–8.765, P  = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025–1.897, P  = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088–3.152, P  = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015–2.359, P  = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017–4.052, P  = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083–6.336, P  = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism.

This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

Peer Review reports

Lung cancer is a prevalent disease that seriously endangers global public health [ 1 , 2 , 3 , 4 ]. According to statistics, there were about 2.20 million newly-diagnosed lung cancer cases and 1.79 million mortalities worldwide every year [ 4 , 5 ]. Lung cancer accounts for more than 20% of cancer-related deaths worldwide, surpassing the combined mortality rates of prostate, breast, and colon cancers [ 1 , 6 , 7 , 8 ]. Despite the progress made in targeted therapy and immunotherapy in the recent decades, platinum-based chemotherapy remains the most widely used treatment option in clinical practice [ 9 , 10 , 11 , 12 ]. However, due to individual variations in sensitivity, only a subset of patients benefits from this treatment [ 13 ]. Given the potential toxic reactions, it is urgent to discover reliable predictive biomarkers to predict the prognosis, therapeutic efficacy and toxicity of lung cancer patients, which is crucial for promoting personalized medicine and enhancing therapeutic outcomes [ 14 , 15 , 16 ].

Cyclins D1 ( CCND1 ) plays a vital role in cell cycle regulation which mediates the G1 to S phase transition [ 17 , 18 , 19 ]. It also has a fundamental involvement in human cancer progression, including cell proliferation, transcription, chromosome duplication and stability, DNA damage response, metabolism, tumor migration and invasion [ 17 , 20 , 21 ]. Multiple clinical studies demonstrated that dysregulation of CCND1 is associated with poor prognosis and platinum-based chemotherapy response in various human cancers, highlighting its potential as a tumor predictive biomarker [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

Single nucleotide polymorphisms (SNPs) refer to DNA sequence polymorphisms caused by single nucleotide variation at the genomic level, accounting for over 90% of all known polymorphisms [ 33 , 34 , 35 ]. Cyclins D1 is the second most frequently amplified locus in human solid tumors [ 36 , 37 ]. The association between CCND1 A870G (rs9344) polymorphism and cancer risk has been previously investigated in lung cancer [ 38 , 39 , 40 , 41 , 42 , 43 ]. However, due to the limited number of studies and sample size, the exact role of CCND1 polymorphism in predicting lung cancer risk remains unclear. Only few studies have been conducted to investigate the correlation between CCND1 rs9344 and platinum-based chemotherapy response in lung cancer.

This study aimed to investigate the association of CCND1 rs9344 with cancer susceptibility, platinum-based chemotherapy, toxicity and overall survival of patients with lung cancer by performing hospital-based case-control study. Additionally, a meta-analysis was conducted using 5432 cases and 6452 control samples to evaluate the association between CCND1 rs9344 polymorphism and lung cancer risk. The results may provide evidence in support of the potential utilization of CCND1 rs9344 as a predictive biomarker for prognosis and chemotherapy sensitivity in Chinese patients with lung cancer in certain conditions.

Study design

During November 2011 to May 2013, 498 patients with primary lung cancer (diagnosed by cytology or histology) were consecutively recruited at Xiangya Hospital and the Affiliated Cancer Hospital of Central South University in Changsha, Hunan Province, China. During the same period, 213 healthy controls were collected from the physical examination center of Xiangya Hospital of Central South University. This study was approved by the Ethics Committee of Xiangya School of Medicine, Central South University (registration number: CTXY-110008-2), and all subjects enrolled have signed the informed consent.

Participants

All patients had been histologically or cytologically confirmed to have primary lung cancer. Subjects who were pregnant, lactating, had active infections, symptomatic brain or leptomeningeal metastases, or other previous or concurrent malignancies were excluded from the study. Among them, 467 patients were enrolled in the platinum-based chemotherapy response study. The inclusion criteria were as follows: (1) They were not administered radiotherapy and/or biological therapy prior to or during chemotherapy; (2) they received at least two cycles of platinum-based chemotherapy; (3) they underwent full follow-up (to March 2017); (4) tumors were assessed before and during treatment using the same imaging methods (Supplementary Table 1 ). Platinum-based chemotherapy regimens include pemetrexed + platinum (PP), gemcitabine + platinum (GP), paclitaxel + platinum (TP), docetaxel + platinum (DP), etoposide + platinum (EP), and other platinum-based chemotherapy regimens (irinotecan + platinum, navibine + platinum). In the case of the healthy controls, individuals with a smoking history, a history of lung ailments, or those engaged in high-risk occupations such as chemical, construction, asbestos, and coal mining work were excluded.

The endpoints of the study were as follows: chemotherapy response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and categorized as responders (complete response: CR, partial response: PR) or non-responders (stable disease: SD and progressive disease: PD). Two professional radiologists independently evaluated the CT scans of lung cancer patients before and after chemotherapy to assess the treatment effectiveness after two cycles of therapy. In case of disagreement, a third radiologist was consulted. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria 3.0 during the first two cycles of chemotherapy regimen. Grade 3 or 4 toxicity was defined as severe toxicity. Severe gastrointestinal toxicity was grade 3 or 4 nausea and vomiting. Severe hematological toxicity included grade 3 or 4 hypochromia, leukopenia, neutropenia and thrombocytopenia. Patients who experienced any type of the grade 3 or 4 toxicities described above were defined as suffering severe overall toxicity.

For the lung caner patients, age, sex, smoking status, stage, histological type, and chemotherapy regimens were collected. For the healthy controls, age, sex and smoking status were collected. The above factors age, sex, smoking status, stage, histological type, and chemotherapy regimens were considered as covaraites in this study.

DNA extraction and genotyping analysis

Venous blood DNA was extracted using the Genomic DNA Purification Kit (Promega, Madison, WI, USA). CCND1 rs9344 was genotyped using the Sequenom MassARRAY System (Sequenom, San Diego, CA, USA).

Study selection and data extraction criteria of meta-analysis

The Pubmed, Embase and Cochrane databases were utilized to identify original studies examing the association between CCND1 rs9344 and lung cancer susceptibility (up to March 29, 2023). The search formula was: “CCND1 or Cyclin D1” and “genetic polymorphism or polymorphisms or variant or rs9344” and “lung cancer”. Included studies had to be original case-control studies with detailed CCND1 rs9344 genotype frequencies or available data. The qualities of selected studies were independently assessed and identified by two researchers. The following information was extracted from the included studies: the last name of the first author, year of publication, country, ethnicity, cancer type, source of cases and controls, number of cases and controls, genotyping method, genotype or allele frequency, and HWE p values for controls.

Statistical analysis

The study size was estimated using Power Analysis and Sample Size (PASS) 2021 (NCSS, LLC. Kaysville, Utah, USA) at a power value of 0.80. The chi-square test was used to assess differences in proportions between groups for the categorical variables. The median age of lung cancer patients, 57 years old, was used as cut-off value. The Hardy-Weinberg equilibrium was calculated using the chi-square test. Associations between CCND1 rs9344 and cancer susceptibility, therapeutic response and toxicity were estimated by unconditional logistic regression. Factors including age, sex, smoking status, stage, histological type, and chemotherapy regimens were considered as covaraites in this study. Survival curves were calculated using the Kaplan-Meier method, and survival analyses were conducted using Cox proportional hazards regression analysis. All significance tests were two-sided, and P <  0.05 was defined as statistically significant. The above analyses were performed using PLINK 1.9 and PASW statistics v18.0 (IBM Co., Armonk, NY, USA).

In the meta-analysis, the association between cancer risk and CCND1 rs9344 was assessed by calculating pooled OR and 95% CI. The heterogeneity of the effect size across studies was estimated and quantified by Cochrane’s Q test and I 2 test. The random effect model is selected if P <  0.1 or I 2  > 50%, otherwise, the fixed effect model is adopted. The stability of the results was assessed by sensitivity analysis. The inverted funnel plot was used to estimate the publication bias. All statistical analysis was performed in R4.2.3. P  < 0.05 was considered statistically significant.

Participants and descriptive data

In this study, 498 cases of lung cancer (394 males and 104 females) and 213 healthy controls (80 males and 133 females) were included. The clinical characteristics of the participants, including sex, age, histology, tumor stage, regimen, therapeutic response and toxicities were listed in Table  1 and Supplementary Table 1 . The genotype distribution of CCND1 rs9344 was in agreement with the Hardy Weinberg equilibrium ( P  = 0.539).

Association between CCND1 rs9344 and lung cancer susceptibility

After adjusting for age and sex, the association between CCND1 rs9344 polymorphism and cancer risk was analyzed in additive, dominant and recessive models, respectively. The results of logistic regression analysis were shown in Table  2 and Supplementary Tables 2 , and the OR values with 95%CI in different genetic models were as follows: additive model (GG vs. GA vs. AA: adjusted OR = 1.115, 95%CI = 0.869–1.431, P  = 0.391); dominant model (GA + AA vs. GG: adjusted OR = 0.980, 95%CI = 0.673–1.425, P  = 0.914); recessive model (AA vs. GG + GA: adjusted OR = 1.498, 95%CI = 0.935–2.399, P  = 0.0927). These results did not indicate a significant correlation between CCND1 rs9344 and the risk of lung cancer.

Subsequently, the stratified analyses were performed. As shown in Fig.  1 and Supplementary Table 3 , CCND1 rs9344 was significantly associated with adenocarcinoma (ADC) patients in the recessive model. The cancer susceptibility was higher in ADC patients with CCND1 rs9344 AA genotypes than in those with GG and GA genotypes (adjusted OR = 1.755, 95%CI = 1.057–2.912, P  = 0.030) (Fig.  1 ).

Stratification analyses of the association of CCND1 rs9344 with lung cancer risk. a – c  Additive ( a ), dominant ( b ), and recessive ( c ) models with adjustments of age and sex. Each box and horizontal line represent the odds ratio (OR) and 95% confidence interval (CI). NSCLC non-small cell lung carcinoma, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer

Association of CCND1 rs9344 and platinum-based chemotherapy response in lung cancer patients

Among the 498 cases of lung cancer, 467 of them had received more than two cycles of platinum-based chemotherapy. As shown in Table  1 and Supplementary Tables 1 , 283 responders and 184 non-responders were included, respectively. The unconditional logistic regression analysis was conducted after adjusting for the age, sex, stage, histological type, smoking status and chemotherapy regimen. However, no significant correlation was identified between CCND1 rs9344 polymorphism and platinum-based chemotherapy response (Table  2 and Supplementary Table 2 ) in the general overall pooled analysis.

However, CCND1 rs9344 was found to be significantly correlated with the platinum-based chemotherapy response of patients who received platinum + pemetrexed therapy (additive model: adjusted OR = 1.926, 95%CI = 1.029–3.605, P  = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428–90.100, P  = 0.022). In addition, a significant correlation was also found between CCND1 rs9344 and platinum-based chemotherapy response in the subgroup of ADC patients (recessive model: adjusted OR = 3.345, 95%CI = 1.276–8.765, P  = 0.014) (Fig.  2 and Supplementary Table 3 ).

Stratification analyses of the association of CCND1 rs9344 with platinum-based chemotherapy response. a – c  Additive ( a ), dominant ( b ), and recessive ( c ) models with adjustments of age, sex, stage, histological type, smoking status, and chemotherapy regimens. Each box and horizontal line represent the odds ratio (OR) and 95% confidence interval (CI). NSCLC non-small cell lung carcinoma, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer. Regimen1, platinum + gemcitabine. Regimen2, platinum + etoposide. Regimen3, platinum + pemetrexed

Association of CCND1 rs9344 with platinum‑based chemotherapy toxicity in lung cancer patients

Of the 467 lung cancer patients who received more than two cycles of platinum-based chemotherapy, 181 had undergone at least one type of severe toxicity. Grade 3–4 gastrointestinal and hematologic toxicities occurred in 101 and 114 patients, respectively (Table  1 and Supplementary Table 1 ). Unconditional logistic regression analysis demonstrated no significant correlation between CCND1 rs9344 and overall toxic reactions (Table  2 and Supplementary Table 2 ). However, CCND1 rs9344 was significantly correlated with overall toxicity in NSCLC patients in both the additive model (adjusted OR = 1.395, 95%CI = 1.025–1.897, P  = 0.034) and the recessive model (adjusted = 1.852, 95%CI = 1.088–3.152, P  = 0.023). The same tendency was also observed in ADC patients, with a significantly increased incidence of overall toxicity in both the additive model (adjusted OR = 1.547, 95%CI = 1.015–2.359, P  = 0.043) and the recessive model (adjusted OR = 2.030, 95%CI = 1.017–4.052, P  = 0.045) (Fig.  3 and Supplementary Table 3 ). The two types of toxicities were then analyzed separately. CCND1 rs9344 was significantly associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083–6.336, P  = 0.035) (Figs.  4 and 5 and Supplementary Table 3 ).

Stratification analyses of CCND1 rs9344 and chemotherapy-induced overall toxicity in lung cancer patients. a – c  Additive ( a ), dominant ( b ), and recessive ( c ) models with adjustments of age, sex, stage, histological type, smoking status, and chemotherapy regimens. Each box and horizontal line represent the odds ratio (OR) and 95% confidence interval (CI). NSCLC non-small cell lung carcinoma, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer. Regimen1, platinum + gemcitabine. Regimen2, platinum + etoposide. Regimen3, platinum + pemetrexed

Stratification analyses of CCND1 rs9344 and chemotherapy-induced gastrointestinal toxicity in lung cancer patients. a – c  Additive ( a ), dominant ( b ), and recessive ( c ) models with adjustments of age, sex, stage, histological type, smoking status, and chemotherapy regimens. Each box and horizontal line represent the odds ratio (OR) and 95% confidence interval (CI). NSCLC non-small cell lung carcinoma, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer. Regimen1, platinum + gemcitabine. Regimen2, platinum + etoposide. Regimen3, platinum + pemetrexed

Stratification analyses of CCND1 rs9344 and chemotherapy-induced hematological toxicity in lung cancer patients. a – c  Additive ( a ), dominant ( b ), and recessive ( c ) models with adjustments of age, sex, stage, histological type, smoking status, and chemotherapy regimens. Each box and horizontal line represent the odds ratio (OR) and 95% confidence interval (CI). NSCLC non-small cell lung carcinoma, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer. Regimen1, platinum + gemcitabine. Regimen2, platinum + etoposide. Regimen3, platinum + pemetrexed

Association of CCND1 rs9344 with 5-year overall survival in lung cancer patients

Finally, we analyzed the correlation between CCND1 rs9344 polymorphism and 5-year overall survival of lung cancer patients. Kaplan-Meier survival analyses were separately performed in three genetic models. Non-significant difference was observed in the 5-year overall survival rate between AA vs. GA vs. GG genotype patients ( P  = 0.226) (Fig.  6 a). We also did not find any significant correlation in the dominant and recessive models (dominant model: HR = 2.268 (0.9057-1.790), P  = 0.268; recessive model: HR = 1.065 (0.7983-1.420), P  = 0.483). Results of multivariate Cox propotional hazards regression were exhibited in Supplementary Table 4 .

Genotype of CCND1 rs9344 and its association with 5-year overall survival. a  AA vs. GA vs. GG; b  AA + GA vs. GG; c  AA vs. GA + GG

A meta-analysis elucidating the relationship between CCND1 rs9344 and lung cancer susceptibility

We then conducted a meta-analysis to assess the association between CCND1 rs9344 and lung cancer susceptibility. Following the process exhibited in Fig.  7 , a total of 104 relevant studies were retrieved according to the search formula, and 10 of them were finally included according to inclusion criteria. Table  3 summarized the characteristics of the selected studies evaluating the association of CCND1 rs9344 with lung cancer susceptibility. A total of 5432 cases and 6452 control samples were included. As seen in Table  4 , the overall OR with 95%CI did not indicate significant differences in the lung cancer risk in random effects (Fig.  8 ) and fixed effect models (Fig.  9 ). The funnel plots were used to check the publication bias, which indicated that there was no significant publication bias (Figs.  10 and 11 ). Both the Begg’s P -value and the Egger’s P -value were not significant (Table  4 ). Sensitivity analyses were performed to check the robustness of the meta-analysis results by neglecting one included study at a time. As shown in Fig.  12 , no single study was found to significantly influence the summary results.

Flow chart of the study selection process

Meta-analyses of correlation between CCND1 rs9344 and lung cancer risk under the random effects model. a  Codominant1 (GA VS GG); b  Codominant2 (AA VS GG); c  Codominant3 (AA VS GA); d  Dominant (AA + GA VS GG); e  Overdominant (GA VS AA + GG); f  Recessive (AA VS GA + GG); g  Allelic (A VS G). The boxes and horizontal lines indicate the risk ratio (RR) and 95% confidence interval (CI), respectively

Meta-analyses of correlation between CCND1 rs9344 and lung cancer risk under the fixed effects model. a  Codominant1 (GA VS GG); b  Codominant2 (AA VS GG); c  Codominant3 (AA VS GA); d  Dominant (AA + GA VS GG); e  Overdominant (GA VS AA + GG); f  Recessive (AA VS GA + GG); g  Allelic (A VS G). The boxes and horizontal lines indicate the risk ratio (RR) and 95% confidence interval (CI), respectively

Funnel plot of  CCND1 rs9344 and lung cancer risk under the random effects model. a  Codominant1 (GA VS GG); b  Codominant2 (AA VS GG); c  Codominant3 (AA VS GA); d  Dominant (AA + GA VS GG); e  Overdominant (GA VS AA + GG); f  Recessive (AA VS GA + GG); g  Allelic (A VS G)

Funnel plot of CCND1 rs9344 and lung cancer risk under the fixed effects model. a  Codominant1 (GA VS GG); b  Codominant2 (AA VS GG); ( c ) Codominant3 (AA VS GA); d  Dominant (AA + GA VS GG); e  Overdominant (GA VS AA + GG); f  Recessive (AA VS GA + GG); g  Allelic (A VS G)

Funnel plot of sensitivity analyses of meta-analysis. The sensitivity analyses were performed by omitting one included study at a time. The boxes and horizontal lines indicate the risk ratio (RR) and 95% confidence interval (CI), respectively

Lung cancer remains one of the leading disease burdens. While the last two decades have witnessed the emergence of novel therapeutic approaches such as targeted therapy and immunotherapy, platinum-based chemotherapy remains the most widely employed treatment for lung cancer patients. However, only a subset of patients could benefit from platinum-based chemotherapy, while the others, who prove insensitive to platinum drugs, endure the burdens of toxic side effects without any associated improvement in survival outcomes. Deeper insight into the pathogenesis, discovery of predictive biomarkers and optimization in therapeutic methods may efficiently improve the treatment outcome [ 48 , 49 , 50 ]. Based on this, one of the issues that urgently need to be addressed now discovering reliable biomarkers to identify individuals with a higher sensitivity to platinum-based chemotherapy. This expansion may provide promising possibilities for lung cancer diagnosis, treatment and prevention.

Unbalanced cycle regulation is one of the hallmarks of carcinogenesis. Cyclin D1 plays a crucial role in the transition from the G1 to the S phase of the cell cycle, thus being widely recognized as a pivotal element during the malignant transformation process [ 51 ]. The rs9344 (A870G), located in exon 4 of CCND1 gene, is a frequent gene polymorphism that regulates alternative splicing and enables the expression of the transcribed Cyclin D1b. The prediction value of CCND1 rs9344 in the prognosis of lung cancer patients has been investigated in several previous studies. However, few of them concentrated on platinum-based chemotherapy response. Hsia, et al. reported that among the lung cancer patients and cancer-free healthy controls, genotype distribution ( P  = 0.0003) and allelic frequency ( P  = 0.0007) of CCND1 rs9344 were significantly different. Individuals who carried the AG and GG genotypes had a 0.59- and 0.52-fold risk of lung cancer compared to the AA genotype, respectively (95% CI, 0.44–0.78 and 0.35–0.79) [ 40 ]. Sobti et al. also indicated that the AG genotype was correlated with a higher risk of lung cancer (OR = 1.7, 95% CI = 0.92–3.14) [ 46 ]. Gautschi, et al. found that CCND1 GG genotype was significantly correlated with platinum-based chemotherapy response ( P  = 0.04), while no significant difference was identified in patients’ prognosis among different genotypes [ 41 ]. However, Cakina, et al. indicated that no correlation was found in CCND1 A870G polymorphism between lung cancer patients and controls [ 43 ].

This study conducted a hospital-based case-control investigation focusing on lung cancer, and systematically investigated the association between CCND1 rs9344 and lung cancer susceptibility, platinum-based chemotherapy sensitivity, toxicity, and overall survival. While no significant differences were observed in the general population, the predictive potential of CCND1 rs9344 was established within specific patient subgroups. For cancer susceptibility, patients with the AA genotype exhibited a significantly higher risk than those with the GG + GA genotype (recessive model, adjusted OR = 1.755, 95%CI = 1.057–2.912, P  = 0.030). In the context of platinum-based chemotherapy, CCND1 rs9344 showed significant correlations with therapy response in patients receiving the PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029–3.605, P  = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428–90.100, P  = 0.022). This significant association was also observed among ADC patients (recessive model: adjusted OR = 3.345, 95%CI = 1.276–8.765, P  = 0.014). Furthermore, an increased risk of overall toxicity was found in both NSCLC (additive model: adjusted OR = 1.395, 95%CI = 1.025–1.897, P  = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088–3.152, P  = 0.023) and ADC patients (additive model: adjusted OR = 1.547, 95%CI = 1.015–2.359, P  = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017–4.052, P  = 0.045). Notably, in non-smokers, CCND1 rs9344 was significantly associated with a higher risk of gastrointestinal toxicity (adjusted OR = 2.620, 95%CI = 1.083–6.336, P  = 0.035).

In addition to the case-control study, a comprehensive meta-analysis for previous research on CCND1 rs9344 and lung cancer susceptibility was conducted. In line with our findings, no significant correlation was observed on a overall scale. This may arise from various factors such as variations in sample selection and distribution, disparities in research quality, substantial heterogeneity in environmental factors, or gene-environment interactions. The results of our study and meta-analysis consistently suggest that the predictive role of CCND1 rs9344 in therapeutic efficacy and prognosis of lung cancer patients may not be effective for all individuals, but rather requires more precise subgroup analysis. Besides, the lack of statistical significance at the overall level may also be caused by various factors in different studies, including differences in sample selection and distribution, variations in study quality, substantial heterogeneity of environmental factors, or gene-environment interactions. The predictive value of CCND1 rs9344 remains to be further validated in large samples through stratified analysis.

To summarize, this study demonstrated that CCND1 rs9344 may be considered a candidate biomarker for cancer susceptibility and therapeutic outcome in certain patient subgroups in Chinese population. Further stratified studies with larger sample sizes are needed to confirm the results.

Availability of data and materials

The data presented in this study are available on request from the corresponding author.

Abbreviations

Adenocarcinoma

Complete response

Progressive disease

Partial response

Stable disease

Single nucleotide polymorphisms

Oliver AL. Lung Cancer: Epidemiology and Screening. Surg Clin North Am. 2022;102:335–44.

Article   PubMed   Google Scholar  

Jenkins R, Walker J. and U. B. Roy 2022 cancer statistics: focus on lung cancer. Future Oncol 2023.

Jakobsen E, Olsen KE, Bliddal M, Hornbak M. Persson and A. Green forecasting lung cancer incidence, mortality, and prevalence to year 2030. BMC Cancer. 2021;21:985.

Article   PubMed   PubMed Central   Google Scholar  

Thai AA, Solomon BJ, Sequist LV, Gainor JF. Heist lung cancer. Lancet. 2021;398:535–54.

Siegel RL, Miller KD. Fuchs and A. Jemal Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

Deshpand R, Chandra M. Rauthan Evolving trends in lung cancer: epidemiology, diagnosis, and management. Indian J Cancer. 2022;59:S90–105.

Harethardottir H, Jonsson S, Gunnarsson O, Hilmarsdottir B, Asmundsson J, Gudmundsdottir I, Saevarsdottir VY, Hansdottir S, Hannesson P. Gudbjartsson [Advances in lung cancer diagnosis and treatment - a review]. Laeknabladid. 2022;108:17–29.

Google Scholar  

Nooreldeen R. and H. Bach Current and Future Development in Lung Cancer diagnosis. Int J Mol Sci 2021; 22.

Hsiao SH, Chen WT, Chung CL, Chou YT, Lin SE, Hong SY, Chang JH. Chang and L. N. Chien comparative survival analysis of platinum-based adjuvant chemotherapy for early-stage squamous cell carcinoma and adenocarcinoma of the lung. Cancer Med. 2022;11:2067–78.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Szejniuk WM, Cekala M, Bogsted M, Meristoudis C, McCulloch; T, Falkmer UG. Roe Adjuvant platinum-based chemotherapy in non-small cell lung cancer: the role of relative dose-intensity and treatment delay. Cancer Treat Res Commun. 2021;27:100318.

Article   CAS   PubMed   Google Scholar  

Griesinger F, Korol EE, Kayaniyil S, Varol N, Ebner T. Goring Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: a meta-analysis. Lung Cancer. 2019;135:196–204.

Zugazagoitia J. Paz-ares extensive-stage small-cell Lung Cancer: first-line and second-line treatment options. J Clin Oncol. 2022;40:671–80.

Liu W, Wang Y, Luo J, Yuan H. Luo Genetic Polymorphisms and platinum-based Chemotherapy-Induced toxicities in patients with Lung Cancer: a systematic review and Meta-analysis. Front Oncol. 2019;9:1573.

Gong WJ, Ma LY, Hu L, Lv YN, Huang H, Xu JQ, Huang DD, Liu RJ, Han Y, Zhang Y, et al. STAT3 rs4796793 contributes to lung cancer risk and clinical outcomes of platinum-based chemotherapy. Int J Clin Oncol. 2019;24:476–84.

Szejniuk WM, Robles AI, McCulloch T, Falkmer UGI. Roe Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art. Pharmacogenomics J. 2019;19:5–14.

Li C, Wang H, Jiang Y, Fu W, Liu X, Zhong R, Cheng B, Zhu F, Xiang Y, He J, et al. Advances in lung cancer screening and early detection. Cancer Biol Med. 2022;19:591–608.

Montalto FI. and F. De Amicis Cyclin D1 in Cancer: a molecular connection for cell cycle control, Adhesion and Invasion in Tumor and Stroma. Cells 2020; 9.

Knudsen ES, Kumarasamy V, Nambiar R, Pearson JD, Vail P, Rosenheck H, Wang J, Eng K, Bremner R, Schramek D, et al. CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities. Cell Rep. 2022;38:110448.

O’Connor MJ, Thakar T, Nicolae CM. Moldovan PARP14 regulates cyclin D1 expression to promote cell-cycle progression. Oncogene. 2021;40:4872–83.

Tchakarska G. Sola the double dealing of cyclin D1. Cell Cycle. 2020;19:163–78.

Zhu D, Huang J, Liu N, Li W. Yan PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration. Cell Death Dis. 2021;12:730.

Lin RJ, Lubpairee T, Liu KY, Anderson DW, Durham S. Poh Cyclin D1 overexpression is associated with poor prognosis in oropharyngeal cancer. J Otolaryngol Head Neck Surg. 2013;42:23.

Zhang B, Liu W, Li L, Lu J, Liu M, Sun Y. Jin KAI1/CD82 and cyclin D1 as biomarkers of invasion, metastasis and prognosis of laryngeal squamous cell carcinoma. Int J Clin Exp Pathol. 2013;6:1060–7.

CAS   PubMed   PubMed Central   Google Scholar  

Ai T, Wang Z, Zhang M, Zhang L, Wang N, Li W. Song expression and prognostic relevance of STAT3 and cyclin D1 in non-small cell lung cancer. Int J Biol Markers. 2012;27:e132–138.

Valla M, Klaestad E, Ytterhus B. Bofin CCND1 amplification in breast Cancer -associations with proliferation, histopathological Grade, Molecular Subtype and Prognosis. J Mammary Gland Biol Neoplasia. 2022;27:67–77.

Ramos-Garcia P, Gil-Montoya JA, Scully C, Ayen A, Gonzalez-Ruiz L, Navarro-Trivino FJ. Gonzalez-Moles an update on the implications of cyclin D1 in oral carcinogenesis. Oral Dis. 2017;23:897–912.

Kuwahara M, Hirai T, Yoshida K, Yamashita Y, Hihara J. Inoue and T. Toge p53, p21(Waf1/Cip1) and cyclin D1 protein expression and prognosis in esophageal cancer. Dis Esophagus. 1999;12:116–9.

Yaylim-Eraltan I, Arikan S, Yildiz Y, Cacina C, Ergen HA, Tuna G, Gormus U. Zeybek and T. Isbir the influence of cyclin D1 A870G polymorphism on colorectal cancer risk and prognosis in a Turkish population. Anticancer Res. 2010;30:2875–80.

CAS   PubMed   Google Scholar  

Holah NS. Hemida Cyclin D1 and PSA act as good prognostic and clinicopathological indicators for breast cancer. J Immunoass Immunochem. 2020;41:28–44.

Article   CAS   Google Scholar  

Liu J, Lin J, Wang X, Zheng X, Gao X, Huang Y, Chen G, Xiong J, Lan B, Chen C, et al. CCND1 amplification profiling identifies a subtype of Melanoma Associated with Poor Survival and an immunosuppressive Tumor Microenvironment. Front Immunol. 2022;13:725679.

Fang L, Xu X, Zheng W, Wu L. Wan the expression of microRNA-340 and cyclin D1 and its relationship with the clinicopathological characteristics and prognosis of lung cancer. Asian J Surg. 2021;44:1363–9.

Li S, Xu J. You the pathologic diagnosis of mantle cell lymphoma. Histol Histopathol. 2021;36:1037–51.

Srinivasan S, Clements JA. Batra single nucleotide polymorphisms in clinics: Fantasy or reality for cancer? Crit Rev Clin Lab Sci. 2016;53:29–39.

Stenzel-Bembenek A, Sagan D, Guz M. Stepulak [Single nucleotide polymorphisms in lung cancer patients and cisplatin treatment]. Postepy Hig Med Dosw (Online). 2014;68:1361–73.

Tebbutt SJ, James A. Pare single-nucleotide polymorphisms and lung disease: clinical implications. Chest. 2007;131:1216–23.

Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.

Qie S. Diehl Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 2016;94:1313–26.

Pandey A, Bahl C, Sharma S, Singh N. Behera Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of north Indian lung cancer patients. Tumori. 2018;104:179–87.

Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, et al. Sequence variants in cell cycle control pathway, X-ray exposure, and lung cancer risk: a multicenter case-control study in Central Europe. Cancer Res. 2006;66:8280–6.

Hsia TC, Liu CJ, Lin CH, Chang WS, Chu CC, Hang LW, Lee HZ. Lo and D. T. Bau Interaction of CCND1 genotype and smoking habit in Taiwan lung cancer patients. Anticancer Res. 2011;31:3601–5.

Gautschi O, Hugli B, Ziegler A, Bigosch C, Bowers NL, Ratschiller D, Jermann M, Stahel RA, Heighway J. Betticher Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Lung Cancer. 2006;51:303–11.

Catarino R, Coelho A, Nogueira A, Araujo A, Gomes M, Lopes C. Medeiros Cyclin D1 polymorphism in non-small cell lung cancer in a Portuguese population. Cancer Biomark. 2012;12:65–72.

Cakina S, Gulyasar T, Ozen A, Sipahi T, Kocak Z. Sener relationship between cyclin D1 (A870G) gene polymorphism and lung cancer. Indian J Biochem Biophys. 2013;50:233–6.

Perez-Morales R, Mendez-Ramirez I, Moreno-Macias H, Mendoza-Posadas AD, Martinez-Ramirez OC, Castro-Hernandez C. Gonsebatt and J. Rubio Genetic susceptibility to lung cancer based on candidate genes in a sample from the Mexican mestizo population: a case-control study. Lung. 2014;192:167–73.

Qiuling S, Yuxin Z, Suhua Z, Cheng X. Shuguang and H. Fengsheng Cyclin D1 gene polymorphism and susceptibility to lung cancer in a Chinese population. Carcinogenesis. 2003;24:1499–503.

Sobti RC, Kaur P, Kaur S, Singh J, Janmeja AK, Jindal SK, Kishan J. Raimondi effects of cyclin D1 (CCND1) polymorphism on susceptibility to lung cancer in a north Indian population. Cancer Genet Cytogenet. 2006;170:108–14.

Wang W, Spitz MR, Yang H, Lu C. Stewart and X. Wu Genetic variants in cell cycle control pathway confer susceptibility to lung cancer. Clin Cancer Res. 2007;13:5974–81.

Purkayastha K, Dhar R, Pethusamy K, Srivastava T, Shankar A. Rath and S. Karmakar the issues and challenges with cancer biomarkers. J Cancer Res Ther. 2023;19:S20–35.

Norris RP, Dew R, Sharp L, Greystoke A, Rice S. Johnell and A. Todd Are there socio-economic inequalities in utilization of predictive biomarker tests and biological and precision therapies for cancer? A systematic review and meta-analysis. BMC Med. 2020;18:282.

Sha D, Jin Z, Budczies J, Kluck K, Stenzinger A. Sinicrope Tumor Mutational Burden as a predictive biomarker in solid tumors. Cancer Discov. 2020;10:1808–25.

Gautschi O, Ratschiller D, Gugger M, Betticher DC. Heighway Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer. 2007;55:1–14.

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Acknowledgements

The authors acknowledge the participants for their contribution to the study.

This work was supported by grants from The National Natural Science Foundation of China (No. 82304634, 82003868). Hubei Provincial Natural Science Foundation of China (No. 2023AFD022, 2020CFB388). Key Research and Development Program of Hubei Province (No.2020BCA060). Scientific Research Projects of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. 2022xhyn055).

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Chao Mei, Baoli Xu, Sanlan Wu, Yongning Lv, Yu Zhang & Weijing Gong

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WG, ZL, YZ and YL contributed to the design of the study. TW, BX, XZ and SW provided help for data collection, CM and WG performed data analysis and manuscript write up. All authors contributed to the article and approved the submitted version.

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Mei, C., Wang, T., Xu, B. et al. Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study. BMC Pulm Med 24 , 167 (2024). https://doi.org/10.1186/s12890-024-02983-1

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DOI : https://doi.org/10.1186/s12890-024-02983-1

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